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Publications Département B3S


  • C. Adam, R. Guérois, A. Citarella, L. Verardi, F. Adolphe, C. Béneut, V. Sommermeyer, C. Ramus, J. Govin, Y. Couté, et V. Borde, « The PHD finger protein Spp1 has distinct functions in the Set1 and the meiotic DSB formation complexes », PLOS Genetics, vol. 14, nᵒ 2, p. e1007223, févr. 2018.

  • A. Barwinska-Sendra, A. Baslé, K. J. Waldron, et S. Un, « A charge polarization model for the metal-specific activity of superoxide dismutases », Physical chemistry chemical physics: PCCP, janv. 2018.
    Résumé : The pathogenicity of Staphylococcus aureus is enhanced by having two superoxide dismutases (SODs): a Mn-specific SOD and another that can use either Mn or Fe. Using 94 GHz electron-nuclear double resonance (ENDOR) and electron double resonance detected (ELDOR)-NMR we show that, despite their different metal-specificities, their structural and electronic similarities extend down to their active-site 1H- and 14N-Mn(ii) hyperfine interactions. However these interactions, and hence the positions of these nuclei, are different in the inactive Mn-reconstituted Escherichia coli Fe-specific SOD. Density functional theory modelling attributes this to a different angular position of the E. coli H171 ligand. This likely disrupts the Mn-H171-E170' triad causing a shift in charge and in metal redox potential, leading to the loss of activity. This is supported by the correlated differences in the Mn(ii) zero-field interactions of the three SOD types and suggests that the triad is important for determining metal specific activity.
    Mots-clés : B3S, BHFMR.

  • A. Boussac, I. Ugur, A. Marion, M. Sugiura, V. R. I. Kaila, et A. W. Rutherford, « The low spin - high spin equilibrium in the S2-state of the water oxidizing enzyme », Biochimica Et Biophysica Acta, vol. 1859, nᵒ 5, p. 342-356, févr. 2018.
    Résumé : In Photosystem II (PSII), the Mn4CaO5-cluster of the active site advances through five sequential oxidation states (S0to S4) before water is oxidized and O2is generated. Here, we have studied the transition between the low spin (LS) and high spin (HS) configurations of S2using EPR spectroscopy, quantum chemical calculations using Density Functional Theory (DFT), and time-resolved UV-visible absorption spectroscopy. The EPR experiments show that the equilibrium between S2LSand S2HSis pH dependent, with a pKa ≈ 8.3 (n ≈ 4) for the native Mn4CaO5and pKa ≈ 7.5 (n ≈ 1) for Mn4SrO5. The DFT results suggest that exchanging Ca with Sr modifies the electronic structure of several titratable groups within the active site, including groups that are not direct ligands to Ca/Sr, e.g., W1/W2, Asp61, His332 and His337. This is consistent with the complex modification of the pKaupon the Ca/Sr exchange. EPR also showed that NH3addition reversed the effect of high pH, NH3-S2LSbeing present at all pH values studied. Absorption spectroscopy indicates that NH3is no longer bound in the S3TyrZstate, consistent with EPR data showing minor or no NH3-induced modification of S3and S0. In both Ca-PSII and Sr-PSII, S2HSwas capable of advancing to S3at low temperature (198 K). This is an experimental demonstration that the S2LSis formed first and advances to S3via the S2HSstate without detectable intermediates. We discuss the nature of the changes occurring in the S2LSto S2HStransition which allow the S2HSto S3transition to occur below 200 K. This work also provides a protocol for generating S3in concentrated samples without the need for saturating flashes.
    Mots-clés : B3S, DFT, EPR, Mn(4)CaO(5) cluster, Oxygen evolution, Photosystem II, PS2, Spin state.

  • M. Byrdin, C. Duan, D. Bourgeois, et K. Brettel, « A Long-Lived Triplet State Is the Entrance Gateway to Oxidative Photochemistry in Green Fluorescent Proteins », Journal of the American Chemical Society, vol. 140, nᵒ 8, p. 2897-2905, févr. 2018.
    Résumé : Though ubiquitously used as selective fluorescence markers in cellular biology, fluorescent proteins (FPs) still have not disclosed all of their surprising properties. One important issue, notably for single-molecule applications, is the nature of the triplet state, suggested to be the starting point for many possible photochemical reactions leading to phenomena such as blinking or bleaching. Here, we applied transient absorption spectroscopy to characterize dark states in the prototypical enhanced green fluorescent protein (EGFP) of hydrozoan origin and, for comparison, in IrisFP, a representative phototransformable FP of anthozoan origin. We identified a long-lived (approximately 5 ms) dark state that is formed with a quantum yield of approximately 1% and has pronounced absorption throughout the visible-NIR range (peak at around 900 nm). Detection of phosphorescence emission with identical kinetics and excitation spectrum allowed unambiguous identification of this state as the first excited triplet state of the deprotonated chromophore. This triplet state was further characterized by determining its phosphorescence emission spectrum, the temperature dependence of its decay kinetics and its reactivity toward oxygen and electron acceptors and donors. It is suggested that it is this triplet state that lies at the origin of oxidative photochemistry in green FPs, leading to phenomena such as so-called "oxidative redding", "primed photoconversion", or, in a manner similar to that previously observed for organic dyes, redox induced blinking control with the reducing and oxidizing system ("ROXS").
    Mots-clés : B3S, LPB.

  • M. Cardoso Dos Santos, J. Goetz, H. Bartenlian, K. - L. Wong, L. J. Charbonnière, et N. Hildebrandt, « Autofluorescence-Free Live-Cell Imaging Using Terbium Nanoparticles », Bioconjugate Chemistry, févr. 2018.

  • F. Celli, A. Petitalot, C. Samson, F. - X. Theillet, et S. Zinn-Justin, « 1 H,13C and15N backbone resonance assignment of the lamin C-terminal region specific to prelamin A », Biomolecular NMR assignments, mars 2018.
    Résumé : Lamins are the main components of the nucleoskeleton. They form a protein meshwork that underlies the inner nuclear membrane. Mutations in the LMNA gene coding for A-type lamins (lamins A and C) cause a large panel of human diseases, referred to as laminopathies. These diseases include muscular dystrophies, lipodystrophies and premature aging diseases. Lamin A exhibits a C-terminal region that is different from lamin C and is post-translationally modified. It is produced as prelamin A and it is then farnesylated, cleaved, carboxymethylated and cleaved again in order to become mature lamin A. In patients with the severe Hutchinson-Gilford progeria syndrome, a specific single point mutation in LMNA leads to an aberrant splicing of the LMNA gene preventing the post-translational processing of prelamin A. This leads to the accumulation of a permanently farnesylated lamin A mutant lacking 50 amino acids named progerin. We here report the NMR1H,15N,13CO,13Cα and13Cβ chemical shift assignment of the C-terminal region that is specific to prelamin A, from amino acid 567 to amino acid 664. We also report the NMR1H,15N,13CO,13Cα and13Cβ chemical shift assignment of the C-terminal region of the progerin variant, from amino acid 567 to amino acid 614. Analysis of these chemical shift data confirms that both prelamin A and progerin C-terminal domains are largely disordered and identifies a common partially populated α-helix from amino acid 576 to amino acid 585. This helix is well conserved from fishes to mammals.
    Mots-clés : B3S, INTGEN, Intrinsically disordered protein, NMR spectroscopy, Nuclear envelope, Nucleoskeleton.

  • H. - J. Chang, P. Mayonove, A. Zavala, A. De Visch, P. Minard, M. Cohen-Gonsaud, et J. Bonnet, « A Modular Receptor Platform To Expand the Sensing Repertoire of Bacteria », ACS synthetic biology, vol. 7, nᵒ 1, p. 166-175, janv. 2018.
    Résumé : Engineered bacteria promise to revolutionize diagnostics and therapeutics, yet many applications are precluded by the limited number of detectable signals. Here we present a general framework to engineer synthetic receptors enabling bacterial cells to respond to novel ligands. These receptors are activated via ligand-induced dimerization of a single-domain antibody fused to monomeric DNA-binding domains (split-DBDs). Using E. coli as a model system, we engineer both transmembrane and cytosolic receptors using a VHH for ligand detection and demonstrate the scalability of our platform by using the DBDs of two different transcriptional regulators. We provide a method to optimize receptor behavior by finely tuning protein expression levels and optimizing interdomain linker regions. Finally, we show that these receptors can be connected to downstream synthetic gene circuits for further signal processing. The general nature of the split-DBD principle and the versatility of antibody-based detection should support the deployment of these receptors into various hosts to detect ligands for which no receptor is found in nature.
    Mots-clés : B3S, MIP.

  • M. David, C. Lebrun, T. Duguet, F. Talmont, R. Beech, S. Orlowski, F. André, R. K. Prichard, et A. Lespine, « Structural model, functional modulation by ivermectin and tissue localization of Haemonchus contortus P-glycoprotein-13 », International Journal for Parasitology. Drugs and Drug Resistance, vol. 8, nᵒ 1, p. 145-157, avr. 2018.
    Résumé : Haemonchus contortus, one of the most economically important parasites of small ruminants, has become resistant to the anthelmintic ivermectin. Deciphering the role of P-glycoproteins in ivermectin resistance is desirable for understanding and overcoming this resistance. In the model nematode, Caenorhabditis elegans, P-glycoprotein-13 is expressed in the amphids, important neuronal structures for ivermectin activity. We have focused on its ortholog in the parasite, Hco-Pgp-13. A 3D model of Hco-Pgp-13, presenting an open inward-facing conformation, has been constructed by homology with the Cel-Pgp-1 crystal structure. In silico docking calculations predicted high affinity binding of ivermectin and actinomycin D to the inner chamber of the protein. Following in vitro expression, we showed that ivermectin and actinomycin D modulated Hco-Pgp-13 ATPase activity with high affinity. Finally, we found in vivo Hco-Pgp-13 localization in epithelial, pharyngeal and neuronal tissues. Taken together, these data suggest a role for Hco-Pgp-13 in ivermectin transport, which could contribute to anthelmintic resistance.
    Mots-clés : ABC transporters, B3S, Haemonchus contortus, Homology modeling, Ivermectin, LPSM, LSOD, Nematode, P-glycoprotein.

  • A. De Muyt, A. Pyatnitskaya, J. Andréani, L. Ranjha, C. Ramus, R. Laureau, A. Fernandez-Vega, D. Holoch, E. Girard, J. Govin, R. Margueron, Y. Couté, P. Cejka, R. Guérois, et V. Borde, « A meiotic XPF–ERCC1-like complex recognizes joint molecule recombination intermediates to promote crossover formation », Genes & Development, vol. 32, nᵒ 3-4, p. 283-296, févr. 2018.

  • Z. Edoo, L. Iannazzo, F. Compain, I. Li de la Sierra Gallay, H. van Tilbeurgh, M. Fonvielle, F. Bouchet, E. Le Run, J. - L. Mainardi, M. Arthur, M. Ethève-Quelquejeu, et J. - E. Hugonnet, « Synthesis of avibactam derivatives and activity on β-lactamases and peptidoglycan biosynthesis enzymes of mycobacteria », Chemistry - A European Journal, mars 2018.

  • S. M. Kapetanaki, M. J. Burton, J. Basran, C. Uragami, P. C. E. Moody, J. S. Mitcheson, R. Schmid, N. W. Davies, P. Dorlet, M. H. Vos, N. M. Storey, et E. Raven, « A mechanism for CO regulation of ion channels », Nature Communications, vol. 9, nᵒ 1, p. 907, 2018.
    Résumé : Despite being highly toxic, carbon monoxide (CO) is also an essential intracellular signalling molecule. The mechanisms of CO-dependent cell signalling are poorly defined, but are likely to involve interactions with heme proteins. One such role for CO is in ion channel regulation. Here, we examine the interaction of CO with KATP channels. We find that CO activates KATP channels and that heme binding to a CXXHX16H motif on the SUR2A receptor is required for the CO-dependent increase in channel activity. Spectroscopic and kinetic data were used to quantify the interaction of CO with the ferrous heme-SUR2A complex. The results are significant because they directly connect CO-dependent regulation to a heme-binding event on the channel. We use this information to present molecular-level insight into the dynamic processes that control the interactions of CO with a heme-regulated channel protein, and we present a structural framework for understanding the complex interplay between heme and CO in ion channel regulation.
    Mots-clés : B3S, LSOD.

  • F. Lallemand, A. Petitalot, S. Vacher, L. de Koning, K. Taouis, B. S. Lopez, S. Zinn-Justin, N. Dalla-Venezia, W. Chemlali, A. Schnitzler, R. Lidereau, I. Bieche, et S. M. Caputo, « Involvement of the FOXO6 transcriptional factor in breast carcinogenesis », Oncotarget, vol. 9, nᵒ 7, p. 7464-7475, janv. 2018.
    Résumé : In mammals, FOXO transcriptional factors form a family of four members (FOXO1, 3, 4, and 6) involved in the modulation proliferation, apoptosis, and carcinogenesis. The role of the FOXO family in breast cancer remains poorly elucidated. According to the cellular context and the stage of the disease, FOXOs can have opposite effects on carcinogenesis. To study the role of FOXOs in breast carcinogenesis in more detail, we examined their expression in normal tissues, breast cell lines, and a large series of breast tumours of human origin. We found a very low physiological level ofFOXO6expression in normal adult tissues and high levels of expression in foetal brain.FOXOgene expressions fluctuate specifically in breast cancer cells compared to normal cells, suggesting that these genes may have different roles in breast carcinogenesis. For the first time, we have shown that, among the variousFOXOgenes, onlyFOXO6was frequently highly overexpressed in breast cell lines and tumours. We also found that inhibition of the endogenous expression of FOXO6 by a specific siRNA inhibited the growth of the human breast cell lines MDA-MB-468 and HCC-38. FACS and Western blot analysis showed that inhibition of endogenous expression of FOXO6 induced accumulation of cells in G0/G1 phase of the cell cycle, but not apoptosis. These results tend to demonstrate that the overexpression of the humanFOXO6gene that we highlighted in the breast tumors stimulates breast carcinogenesis by activating breast cancer cell proliferation.
    Mots-clés : B3S, cervical squamous cell carcinoma, endometrial adenocarcinoma, gynecological cancers, INTGEN, prognosis, uc.189.

  • L. Lecoq, S. Wang, T. Wiegand, S. Bressanelli, M. Nassal, B. H. Meier, et A. Böckmann, « Localizing conformational hinges by NMR: where do HBV core proteins adapt for capsid assembly? », ChemPhysChem, mars 2018.

  • L. Lecoq, S. Wang, T. Wiegand, S. Bressanelli, M. Nassal, B. H. Meier, et A. Böckmann, « Solid-state [13C-15N] NMR resonance assignment of hepatitis B virus core protein », Biomolecular NMR assignments, vol. 12, nᵒ 1, p. 205-214, avr. 2018.
    Résumé : Each year, nearly 900,000 deaths are due to serious liver diseases caused by chronic hepatitis B virus infection. The viral particle is composed of an outer envelope and an inner icosahedral nucleocapsid formed by multiple dimers of a ~ 20 kDa self-assembling core protein (Cp). Here we report the solid-state 13C and 15N resonance assignments of the assembly domain, Cp149, of the core protein in its capsid form. A secondary chemical shift analysis of the 140 visible residues suggests an overall alpha-helical three-dimensional fold matching that derived for Cp149 from the X-ray crystallography of the capsid, and from solution-state NMR of the Cp149 dimer. Interestingly, however, at three distinct regions the chemical shifts in solution differ significantly between core proteins in the capsid state versus in the dimer state, strongly suggesting the respective residues to be involved in capsid assembly.
    Mots-clés : AMIG, Assignments, B3S, Core protein, Hepatitis B virus, IMAPP, Nucleocapsid, Solid-state NMR.

  • M. J. Llansola-Portoles, K. Redeckas, S. Streckaité, C. Ilioaia, A. A. Pascal, A. Telfer, M. Vengris, L. Valkunas, et B. Robert, « Lycopene crystalloids exhibit singlet exciton fission in tomatoes », Physical Chemistry Chemical Physics, vol. 20, nᵒ 13, p. 8640-8646, 2018.

  • A. A. Nadaradjane, R. Guerois, et J. Andreani, « Protein-Protein Docking Using Evolutionary Information », in Protein Complex Assembly, vol. 1764, J. A. Marsh, Éd. New York, NY: Springer New York, 2018, p. 429-447.

  • T. Meyer, A. Vigouroux, M. Aumont-Niçaise, G. Comte, L. Vial, C. Lavire, et S. Morera, « The plant defense signal galactinol is specifically used as a nutrient by the bacterial pathogen Agrobacterium fabrum », The Journal of Biological Chemistry, mars 2018.
    Résumé : The bacterial plant pathogen Agrobacterium fabrum uses periplasmic binding proteins (PBPs) along with ABC transporters to import a wide variety of plant molecules as nutrients. Nonetheless, how A. fabrum acquires plant metabolites is incompletely understood. Using genetic approaches and affinity measurements, we identified here the PBP MelB and its transporter as being responsible for the uptake of the raffinose family of oligosaccharides (RFOs), which are the most widespread Dgalactose containing oligosaccharides in higher plants. We also found that the RFO precursor galactinol, recently described as a plant defense molecule, is imported into Agrobacterium via MelB with nanomolar range affinity. Structural analyses and binding mode comparisons of the X-ray structures of MelB in complex with raffinose, stachyose, galactinol, galactose and melibiose (a raffinose degradation product) revealed how MelB recognizes the nonreducing end galactose common to all these ligands and that MelB has a strong preference for a two-unit sugar ligand. Of note, MelB conferred a competitive advantage to A. fabrum in colonizing the rhizosphere of tomato plants. Our integrative work highlights the structural and functional characteristics of melibiose and galactinol assimilation by A. fabrum, leading to a competitive advantage for these bacteria in the rhizosphere. We propose that the PBP MelB, which is highly conserved among both symbionts and pathogens from Rhizobiace family, is a major trait in these bacteria required for early steps of plant colonization.
    Mots-clés : ABC transporter, agrobacterium, B3S, bacteria, crystal structure, galactinol, MESB3S, microbiology, periplasmic binding protein, PF, PIM, RFOs, sugar transport.

  • P. Müller, E. Ignatz, S. Kiontke, K. Brettel, et L. - O. Essen, « Sub-nanosecond tryptophan radical deprotonation mediated by a protein-bound water cluster in class II DNA photolyases », Chemical Science, vol. 9, nᵒ 5, p. 1200-1212, 2018.

  • D. P. O'Brien, A. C. S. Perez, J. Karst, S. E. Cannella, V. Y. N. Enguéné, A. Hessel, D. Raoux-Barbot, A. Voegele, O. Subrini, M. Davi, J. I. Guijarro, B. Raynal, B. Baron, P. England, B. Hernandez, M. Ghomi, V. Hourdel, C. Malosse, J. Chamot-Rooke, P. Vachette, D. Durand, S. Brier, D. Ladant, et A. Chenal, « Calcium-dependent disorder-to-order transitions are central to the secretion and folding of the CyaA toxin of Bordetella pertussis, the causative agent of whooping cough », Toxicon: Official Journal of the International Society on Toxinology, janv. 2018.
    Résumé : The adenylate cyclase toxin (CyaA) plays an essential role in the early stages of respiratory tract colonization by Bordetella pertussis, the causative agent of whooping cough. Once secreted, CyaA invades eukaryotic cells, leading to cell death. The cell intoxication process involves a unique mechanism of translocation of the CyaA catalytic domain directly across the plasma membrane of the target cell. Herein, we review our recent results describing how calcium is involved in several steps of this intoxication process. In conditions mimicking the low calcium environment of the crowded bacterial cytosol, we show that the C-terminal, calcium-binding Repeat-in-ToXin (RTX) domain of CyaA, RD, is an extended, intrinsically disordered polypeptide chain with a significant level of local, secondary structure elements, appropriately sized for transport through the narrow channel of the secretion system. Upon secretion, the high calcium concentration in the extracellular milieu induces the refolding of RD, which likely acts as a scaffold to favor the refolding of the upstream domains of the full-length protein. Due to the presence of hydrophobic regions, CyaA is prone to aggregate into multimeric forms in vitro, in the absence of a chaotropic agent. We have recently defined the experimental conditions required for CyaA folding, comprising both calcium binding and molecular confinement. These parameters are critical for CyaA folding into a stable, monomeric and functional form. The monomeric, calcium-loaded (holo) toxin exhibits efficient liposome permeabilization and hemolytic activities in vitro, even in a fully calcium-free environment. By contrast, the toxin requires sub-millimolar calcium concentrations in solution to translocate its catalytic domain across the plasma membrane, indicating that free calcium in solution is actively involved in the CyaA toxin translocation process. Overall, this data demonstrates the remarkable adaptation of bacterial RTX toxins to the diversity of calcium concentrations it is exposed to in the successive environments encountered in the course of the intoxication process.
    Mots-clés : B3S, Bordetella pertussis, Calcium, CyaA toxin, Disorder-to-order transition, FAAM, Folding, Protein secretion, Whooping cough.

  • C. Orelle, C. Durmort, K. Mathieu, B. Duchêne, S. Aros, F. Fenaille, F. André, C. Junot, T. Vernet, et J. - M. Jault, « A multidrug ABC transporter with a taste for GTP », Scientific Reports, vol. 8, nᵒ 1, p. 2309, févr. 2018.
    Résumé : During the evolution of cellular bioenergetics, many protein families have been fashioned to match the availability and replenishment in energy supply. Molecular motors and primary transporters essentially need ATP to function while proteins involved in cell signaling or translation consume GTP. ATP-Binding Cassette (ABC) transporters are one of the largest families of membrane proteins gathering several medically relevant members that are typically powered by ATP hydrolysis. Here, a Streptococcus pneumoniae ABC transporter responsible for fluoroquinolones resistance in clinical settings, PatA/PatB, is shown to challenge this concept. It clearly favors GTP as the energy supply to expel drugs. This preference is correlated to its ability to hydrolyze GTP more efficiently than ATP, as found with PatA/PatB reconstituted in proteoliposomes or nanodiscs. Importantly, the ATP and GTP concentrations are similar in S. pneumoniae supporting the physiological relevance of GTP as the energy source of this bacterial transporter.
    Mots-clés : B3S, LSOD.

  • M. Parlato, F. Charbit-Henrion, J. Pan, C. Romano, R. Duclaux-Loras, M. - H. Le Du, N. Warner, P. Francalanci, J. Bruneau, M. Bras, M. Zarhrate, B. Bègue, N. Guegan, S. Rakotobe, N. Kapel, P. De Angelis, A. M. Griffiths, K. Fiedler, E. Crowley, F. Ruemmele, A. M. Muise, et N. Cerf-Bensussan, « Human ALPI deficiency causes inflammatory bowel disease and highlights a key mechanism of gut homeostasis », EMBO molecular medicine, mars 2018.
    Résumé : Herein, we report the first identification of biallelic-inherited mutations inALPIas a Mendelian cause of inflammatory bowel disease in two unrelated patients.ALPIencodes for intestinal phosphatase alkaline, a brush border metalloenzyme that hydrolyses phosphate from the lipid A moiety of lipopolysaccharides and thereby drastically reduces Toll-like receptor 4 agonist activity. Prediction tools and structural modelling indicate that all mutations affect critical residues or inter-subunit interactions, and heterologous expression in HEK293T cells demonstrated that allALPImutations were loss of function.ALPImutations impaired either stability or catalytic activity of ALPI and rendered it unable to detoxify lipopolysaccharide-dependent signalling. Furthermore, ALPI expression was reduced in patients' biopsies, and ALPI activity was undetectable in ALPI-deficient patient's stool. Our findings highlight the crucial role of ALPI in regulating host-microbiota interactions and restraining host inflammatory responses. These results indicate thatALPImutations should be included in screening for monogenic causes of inflammatory bowel diseases and lay the groundwork for ALPI-based treatments in intestinal inflammatory disorders.
    Mots-clés : B3S, inflammatory bowel diseases, intestinal phosphatase alkaline, INTGEN, monogenic disease.

  • J. A. Romero-Espinoza, Y. Moreno-Valencia, R. H. Coronel-Tellez, M. Castillejos-Lopez, A. Hernandez, A. Dominguez, A. Miliar-Garcia, A. Barbachano-Guerrero, R. Perez-Padilla, A. Alejandre-Garcia, et J. A. Vazquez-Perez, « Virome and bacteriome characterization of children with pneumonia and asthma in Mexico City during winter seasons 2014 and 2015 », PLOS ONE, vol. 13, nᵒ 2, p. e0192878, févr. 2018.

  • H. Safya, A. Mellouk, J. Legrand, S. M. Le Gall, M. Benbijja, C. Kanellopoulos-Langevin, J. M. Kanellopoulos, et P. Bobé, « Variations in Cellular Responses of Mouse T Cells to Adenosine-5'-Triphosphate Stimulation Do Not Depend on P2X7 Receptor Expression Levels but on Their Activation and Differentiation Stage », Frontiers in Immunology, vol. 9, p. 360, 2018.
    Résumé : A previous report has shown that regulatory T cells (Treg) were markedly more sensitive to adenosine-5'-triphosphate (ATP) than conventional T cells (Tconv). Another one has shown that Tregs and CD45RBlowTconvs, but not CD45RBhighTconvs, displayed similar high sensitivity to ATP. We have previously reported that CD45RBlowTconvs expressing B220/CD45RABC molecules in a pre-apoptotic stage are resistant to ATP stimulation due to the loss of P2X7 receptor (P2X7R) membrane expression. To gain a clearer picture on T-cell sensitivity to ATP, we have quantified four different cellular activities triggered by ATP in mouse T cells at different stages of activation/differentiation, in correlation with levels of P2X7R membrane expression. P2X7R expression significantly increases on Tconvs during differentiation from naive CD45RBhighCD44lowto effector/memory CD45RBlowCD44highstage. Maximum levels of upregulation are reached on recently activated CD69+naive and memory Tconvs. Ectonucleotidases CD39 and CD73 expression levels increase in parallel with those of P2X7R. Recently activated CD69+CD45RBhighCD44lowTconvs, although expressing high levels of P2X7R, fail to cleave homing receptor CD62L after ATP treatment, but efficiently form pores and externalize phosphatidylserine (PS). In contrast, naive CD45RBhighCD44lowTconvs cleave CD62L with high efficiency although they express a lower level of P2X7, thus suggesting that P2X7R levels are not a limiting factor for signaling ATP-induced cellular responses. Contrary to common assumption, P2X7R-mediated cellular activities in mouse Tconvs are not triggered in an all-or-none manner, but depend on their stage of activation/differentiation. Compared to CD45RBlowTconvs, CD45RBlowFoxp3+Tregs show significantly higher levels of P2X7R membrane expression and of sensitivity to ATP as evidenced by their high levels of CD62L shedding, pore formation and PS externalization observed after ATP treatment. In summary, the different abilities of ATP-treated Tconvs to form pore or cleave CD62L depending on their activation and differentiation state suggests that P2X7R signaling varies according to the physiological role of T convs during antigen activation in secondary lymphoid organs or trafficking to inflammatory sites.
    Mots-clés : B3S, CD39, CD62L shedding, CD73, cell death, MIP, P2X7, phosphatidyslerine exposure, pore formation, regulatory T lymphocyte.

  • R. R. Sonani, A. Gardiner, R. P. Rastogi, R. Cogdell, B. Robert, et D. Madamwar, « Site, trigger, quenching mechanism and recovery of non-photochemical quenching in cyanobacteria: recent updates », Photosynthesis Research, mars 2018.

  • C. Tellier-Lebegue, E. Dizet, E. Ma, X. Veaute, E. Coïc, J. - B. Charbonnier, et L. Maloisel, « Correction: The translesion DNA polymerases Pol ζ and Rev1 are activated independently of PCNA ubiquitination upon UV radiation in mutants of DNA polymerase δ », PLoS genetics, vol. 14, nᵒ 2, p. e1007236, févr. 2018.
    Résumé : [This corrects the article DOI: 10.1371/journal.pgen.1007119.].
    Mots-clés : B3S, INTGEN.

  • T. - T. Tran, M. - H. Ha-Thi, T. Pino, A. Quaranta, C. Lefumeux, W. Leibl, et A. Aukauloo, « Snapshots of Light Induced Accumulation of Two Charges on Methylviologen using a Sequential Nanosecond Pump–Pump Photoexcitation », The Journal of Physical Chemistry Letters, vol. 9, nᵒ 5, p. 1086-1091, 2018.


  • A. M. Acuña, C. Lemaire, R. van Grondelle, B. Robert, et I. H. M. van Stokkum, « Energy transfer and trapping in Synechococcus WH 7803 », Photosynthesis Research, oct. 2017.
    Résumé : Excitation energy transfer (EET) and trapping in Synechococcus WH 7803 whole cells and isolated photosystem I (PSI) complexes have been studied by time-resolved emission spectroscopy at room temperature (RT) and at 77 K. With the help of global and target analysis, the pathways of EET and the charge separation dynamics have been identified. Energy absorbed in the phycobilisome (PB) rods by the abundant phycoerythrin (PE) is funneled to phycocyanin (PC645) and from there to the core that contains allophycocyanin (APC660 and APC680). Intra-PB EET rates have been estimated to range from 11 to 68/ns. It was estimated that at RT, the terminal emitter of the phycobilisome, APC680, transfers its energy at a rate of 90/ns to PSI and at a rate of 50/ns to PSII. At 77 K, the redshifted Chl a states in the PSI core were heterogeneous, with maximum emission at 697 and 707 nm. In 72% of the PSI complexes, the bulk Chl a in equilibrium with F697 decayed with a main trapping lifetime of 39 ps.
    Mots-clés : B3S, Excitation energy transfer, Global analysis, LBMS, Light harvesting, LPSM, Target analysis.

  • M. Amjadi, T. Hallaj, H. Asadollahi, Z. Song, M. de Frutos, et N. Hildebrandt, « Facile synthesis of carbon quantum dot/silver nanocomposite and its application for colorimetric detection of methimazole », Sensors and Actuators B: Chemical, vol. 244, p. 425-432, 2017.

  • H. Azouaoui, C. Montigny, T. Dieudonné, P. Champeil, A. Jacquot, J. L. Vázquez-Ibar, P. Le Maréchal, J. Ulstrup, M. - R. Ash, J. A. Lyons, P. Nissen, et G. Lenoir, « A High and Phosphatidylinositol-4-phosphate (PI4P)-dependent ATPase Activity for the Drs2p/Cdc50p Flippase after Removal of its N- and C-terminal Extensions », Journal of Biological Chemistry, p. jbc.M116.751487, mars 2017.
    Mots-clés : autophosphorylation, B3S, Cdc50 protein, Flippase, inhibition mechanism, limited proteolysis, lipid-protein interaction, LPSM, phosphatidylserine, phosphoinositide.

  • A. Bahloul, E. Pepermans, B. Raynal, N. Wolff, F. Cordier, P. England, S. Nouaille, B. Baron, A. El-Amraoui, J. - P. Hardelin, D. Durand, et C. Petit, « Conformational switch of harmonin, a submembrane scaffold protein of the hair cell mechanoelectrical transduction machinery », FEBS letters, juin 2017.
    Résumé : Mutations in the gene encoding harmonin, a multi-PDZ domain-containing submembrane protein, cause Usher syndrome type 1 (congenital deafness and balance disorder, as well as early-onset sight loss). The structure of the protein and biological activities of its three different classes of splice isoforms (a, b, and c) remain poorly understood. Combining biochemical and biophysical analyses, we show that harmonin-a1 can switch between open and closed conformations through intramolecular binding of its C-terminal PDZ-binding motif to its N-terminal supramodule NTD-PDZ1 and a flexible PDZ2-PDZ3 linker. This conformational switch presumably extends to most harmonin isoforms, and is expected to have an impact on the interaction with some binding partners, as shown here for cadherin-related 23, another component of the hair cell mechanoelectrical transduction machinery. This article is protected by copyright. All rights reserved.
    Mots-clés : B3S, conformation switch, FAAM, PDZ domain, Usher syndrome.

  • E. Baquero, A. A. Albertini, H. Raux, A. Abou‐Hamdan, E. Boeri‐Erba, M. Ouldali, L. Buonocore, J. K. Rose, J. Lepault, S. Bressanelli, et Y. Gaudin, « Structural intermediates in the fusion‐associated transition of vesiculovirus glycoprotein », The EMBO Journal, vol. 36, nᵒ 5, p. 679-692, mars 2017.
    Mots-clés : B3S, conformational change, glycoprotein, IMAPP, intermediate structures, membrane fusion, RHABDO, Vesiculovirus, VIRO, VIROEM.

  • L. Benkaidali, F. André, G. Moroy, B. Tangour, F. Maurel, et M. Petitjean, « The Cytochrome P450 3A4 Has Three Major Conformations: New Clues to Drug Recognition by this Promiscuous Enzyme », Molecular Informatics, juill. 2017.
    Résumé : We computed the channels of the 3A4 isoform of the cytochrome P450 3A4 (CYP) on the basis of 24 crystal structures extracted from the Protein Data Bank (PDB). We identified three major conformations (denoted C, O1 and O2) using an enhanced version of the CCCPP software that we developed for the present work, while only two conformations (C and O(2) ) are considered in the literature. We established the flowchart of definition of these three conformations in function of the structural and physicochemical parameters of the ligand. The channels are characterized with qualitative and quantitative parameters, and not only with their surrounding secondary structures as it is usually done in the literature.
    Mots-clés : active site access channels, B3S, conformations, CYP 3A4 ligands, cytochromes P450, drug-drug interactions, LSOD.

  • S. Bhuckory, E. Hemmer, Y. - T. Wu, A. Yahia-Ammar, F. Vetrone, et N. Hildebrandt, « Core or Shell? Er <sup>3+</sup> FRET Donors in Upconversion Nanoparticles: Core or Shell? Er <sup>3+</sup> FRET Donors in Upconversion Nanoparticles », European Journal of Inorganic Chemistry, vol. 2017, nᵒ 44, p. 5186-5195, déc. 2017.

  • D. A. Braun, J. Rao, G. Mollet, D. Schapiro, M. - C. Daugeron, W. Tan, O. Gribouval, O. Boyer, P. Revy, T. Jobst-Schwan, J. M. Schmidt, J. A. Lawson, D. Schanze, S. Ashraf, J. F. P. Ullmann, C. A. Hoogstraten, N. Boddaert, B. Collinet, G. Martin, D. Liger, S. Lovric, M. Furlano, I. C. Guerrera, O. Sanchez-Ferras, J. F. Hu, A. - C. Boschat, S. Sanquer, B. Menten, S. Vergult, N. De Rocker, M. Airik, T. Hermle, S. Shril, E. Widmeier, H. Y. Gee, W. - I. Choi, C. E. Sadowski, W. L. Pabst, J. K. Warejko, A. Daga, T. Basta, V. Matejas, K. Scharmann, S. D. Kienast, B. Behnam, B. Beeson, A. Begtrup, M. Bruce, G. - S. Ch'ng, S. - P. Lin, J. - H. Chang, C. - H. Chen, M. T. Cho, P. M. Gaffney, P. E. Gipson, C. - H. Hsu, J. A. Kari, Y. - Y. Ke, C. Kiraly-Borri, W. - M. Lai, E. Lemyre, R. O. Littlejohn, A. Masri, M. Moghtaderi, K. Nakamura, F. Ozaltin, M. Praet, C. Prasad, A. Prytula, E. R. Roeder, P. Rump, R. E. Schnur, T. Shiihara, M. D. Sinha, N. A. Soliman, K. Soulami, D. A. Sweetser, W. - H. Tsai, J. - D. Tsai, R. Topaloglu, U. Vester, D. H. Viskochil, N. Vatanavicharn, J. L. Waxler, K. J. Wierenga, M. T. F. Wolf, S. - N. Wong, S. A. Leidel, G. Truglio, P. C. Dedon, A. Poduri, S. Mane, R. P. Lifton, M. Bouchard, P. Kannu, D. Chitayat, D. Magen, B. Callewaert, H. van Tilbeurgh, M. Zenker, C. Antignac, et F. Hildebrandt, « Mutations in KEOPS-complex genes cause nephrotic syndrome with primary microcephaly », Nature Genetics, août 2017.
    Résumé : Galloway-Mowat syndrome (GAMOS) is an autosomal-recessive disease characterized by the combination of early-onset nephrotic syndrome (SRNS) and microcephaly with brain anomalies. Here we identified recessive mutations in OSGEP, TP53RK, TPRKB, and LAGE3, genes encoding the four subunits of the KEOPS complex, in 37 individuals from 32 families with GAMOS. CRISPR-Cas9 knockout in zebrafish and mice recapitulated the human phenotype of primary microcephaly and resulted in early lethality. Knockdown of OSGEP, TP53RK, or TPRKB inhibited cell proliferation, which human mutations did not rescue. Furthermore, knockdown of these genes impaired protein translation, caused endoplasmic reticulum stress, activated DNA-damage-response signaling, and ultimately induced apoptosis. Knockdown of OSGEP or TP53RK induced defects in the actin cytoskeleton and decreased the migration rate of human podocytes, an established intermediate phenotype of SRNS. We thus identified four new monogenic causes of GAMOS, describe a link between KEOPS function and human disease, and delineate potential pathogenic mechanisms.
    Mots-clés : ARCHEE, B3S, FAAM, MICROBIO.

  • K. Brettel, M. Byrdin, et M. H. Vos, « Ultrafast Light-Induced Processes in DNA Photolyase and Its Substrate-Bound Complex », in Ultrafast Dynamics at the Nanoscale: Biomolecules and Supramolecular Assemblies, I. Burghardt et S. Haacke, Éd. Penthouse Level, Suntec Tower 3, 8 Temasek Boulevard, Singapore 038988: Pan Stanford Publishing, 2017, p. 65-90.

  • Ultrafast Dynamics at the Nanoscale: Biomolecules and Supramolecular Assemblies. Penthouse Level, Suntec Tower 3, 8 Temasek Boulevard, Singapore 038988: Pan Stanford Publishing, 2017.

  • C. Caillet-Saguy, A. Toto, R. Guerois, P. Maisonneuve, E. di Silvio, K. Sawyer, S. Gianni, et N. Wolff, « Regulation of the Human Phosphatase PTPN4 by the inter-domain linker connecting the PDZ and the phosphatase domains », Scientific Reports, vol. 7, nᵒ 1, p. 7875, août 2017.
    Résumé : Human protein tyrosine phosphatase non-receptor type 4 (PTPN4) has been shown to prevent cell death. The active form of human PTPN4 consists of two globular domains, a PDZ (PSD-95/Dlg/ZO-1) domain and a phosphatase domain, tethered by a flexible linker. Targeting its PDZ domain abrogates this protection and triggers apoptosis. We previously demonstrated that the PDZ domain inhibits the phosphatase activity of PTPN4 and that the mere binding of a PDZ ligand is sufficient to release the catalytic inhibition. We demonstrate here that the linker connecting the PDZ domain and the phosphatase domain is involved in the regulation of the phosphatase activity in both PDZ-related inhibition and PDZ ligand-related activation events. We combined bioinformatics and kinetic studies to decipher the role of the linker in the PTPN4 activity. By comparing orthologous sequences, we identified a conserved patch of hydrophobic residues in the linker. We showed that mutations in this patch affect the regulation of the PTPN4 bidomain indicating that the PDZ-PDZ ligand regulation of PTPN4 is a linker-mediated mechanism. However, the mutations do not alter the binding of the PDZ ligand. This study strengthens the notion that inter-domain linker can be of functional importance in enzyme regulation of large multi-domain proteins.
    Mots-clés : AMIG, B3S.

  • S. E. Cannella, V. Y. Ntsogo Enguéné, M. Davi, C. Malosse, A. C. Sotomayor Pérez, J. Chamot-Rooke, P. Vachette, D. Durand, D. Ladant, et A. Chenal, « Stability, structural and functional properties of a monomeric, calcium–loaded adenylate cyclase toxin, CyaA, from Bordetella pertussis », Scientific Reports, vol. 7, p. 42065, févr. 2017.

  • L. Cao, S. Cantos-Fernandes, et B. Gigant, « The structural switch of nucleotide-free kinesin », Scientific Reports, vol. 7, p. 42558, févr. 2017.

  • P. Cardol et A. Krieger-Liszkay, « From light capture to metabolic needs, oxygenic photosynthesis is an ever-expanding field of study in plants, algae and cyanobacteria », Physiologia Plantarum, mai 2017.
    Résumé : Understanding of the molecular mechanisms of photosynthetic electron and proton transports and their regulation in plants and algae in response to changes in environmental conditions is an important issue for fundamental research on photosynthesis, and may extend even to practical applications by identifying important sites for improvement of photosynthesis. The significance and often centrality of regulatory mechanisms of photosynthetic electron transport is well established for processes in plant acclimation. In recent years, significant advancements have been achieved in understanding of regulatory processes such as dissipation of excess energy in the antenna systems, state transitions, cyclic electron flow, oxygen reduction by flavodiiron enzymes and many others.
    Mots-clés : B3S, MROP.

  • M. - F. Carlier et S. Shekhar, « Global treadmilling coordinates actin turnover and controls the size of actin networks », Nature Reviews Molecular Cell Biology, mars 2017.

  • L. Celma, C. Corbinais, J. Vercruyssen, X. Veaute, I. L. de la Sierra-Gallay, R. Guérois, D. Busso, A. Mathieu, S. Marsin, S. Quevillon-Cheruel, et J. P. Radicella, « Structural basis for the substrate selectivity of Helicobacter pylori NucT nuclease activity », PLOS ONE, vol. 12, nᵒ 12, p. e0189049, déc. 2017.

  • V. Chaptal, F. Delolme, A. Kilburg, S. Magnard, C. Montigny, M. Picard, C. Prier, L. Monticelli, O. Bornert, M. Agez, S. Ravaud, C. Orelle, R. Wagner, A. Jawhari, I. Broutin, E. Pebay-Peyroula, J. - M. Jault, H. R. Kaback, M. le Maire, et P. Falson, « Quantification of Detergents Complexed with Membrane Proteins », Scientific Reports, vol. 7, p. 41751, févr. 2017.

  • J. - P. Charbonnier, E. M. van Rikxoort, A. A. A. Setio, C. M. Schaefer-Prokop, B. van Ginneken, et F. Ciompi, « Improving airway segmentation in computed tomography using leak detection with convolutional networks », Medical Image Analysis, vol. 36, p. 52-60, 2017.

  • A. Chevrel, A. Mesneau, D. Sanchez, L. Celma, S. Quevillon-Cheruel, A. Cavagnino, S. Nessler, I. Li de la Sierra-Gallay, H. van Tilbeurgh, P. Minard, M. Valerio-Lepiniec, et A. Urvoas, « Alpha Repeat proteins (αRep) as expression and crystallization helpers », Journal of Structural Biology, août 2017.
    Résumé : We have previously described a highly diverse library of artificial repeat proteins based on thermostable HEAT-like repeats, named αRep. αReps binding specifically to proteins difficult to crystallize have been selected and in several examples, they made possible the crystallization of these proteins. To further simplify the production and crystallization experiments we have explored the production of chimeric protein corresponding to covalent association between the targets and their specific binders strengthened by a linker. Although chimeric proteins with expression partners are classically used to enhance expression these fusions cannot usually be used for crystallization. With specific expression partners like a cognate αRep this is no longer true, and chimeric proteins can be expressed purified and crystallized. αRep selection by phage display suppose that at least a small amount of the target protein should be produced to be used as a bait for selection and this might, in some cases, be difficult. We have therefore transferred the αRep library in a new construction adapted to selection by protein complementation assay (PCA). This new procedure allows to select specific binders by direct interaction with the target in the cytoplasm of the bacteria and consequently does not require preliminary purification of target protein. αRep binders selected by PCA or by phage display can be used to enhance expression, stability, solubility and crystallogenesis of proteins that are otherwise difficult to express, purify and/or crystallize.
    Mots-clés : artificial repeat proteins, B3S, Crystallization helper, FAAM, Fusion protein, MIP, Protein complementation assay, Protein library.

  • M. Clémancey, T. Cantat, G. Blondin, J. - M. Latour, P. Dorlet, et G. Lefèvre, « Structural Insights into the Nature of Fe(0) and Fe(I) Low-Valent Species Obtained upon the Reduction of Iron Salts by Aryl Grignard Reagents », Inorganic Chemistry, vol. 56, nᵒ 7, p. 3834-3848, avr. 2017.
    Résumé : Mechanistic studies of the reduction of Fe(III) and Fe(II) salts by aryl Grignard reagents in toluene/tetrahydrofuran mixtures in the absence of a supporting ligand, as well as structural insights regarding the nature of the low-valent iron species obtained at the end of this reduction process, are reported. It is shown that several reduction pathways can be followed, depending on the starting iron precursor. We demonstrate, moreover, that these pathways lead to a mixture of Fe(0) and Fe(I) complexes regardless of the nature of the precursor. Mössbauer and (1)H NMR spectroscopies suggest that diamagnetic 16-electron bisarene complexes such as (η(4)-C6H5Me)2Fe(0) can be formed as major species (85% of the overall iron quantity). The formation of a η(6)-arene-ligated low-spin Fe(I) complex as a minor species (accounting for ca. 15% of the overall iron quantity) is attested by Mössbauer spectroscopy, as well as by continuous-wave electron paramagnetic resonance (EPR) and pulsed-EPR (HYSCORE) spectroscopies. The nature of the Fe(I) coordination sphere is discussed by means of isotopic labeling experiments and density functional theory calculations. It is shown that the most likely low-spin Fe(I) candidate obtained in these systems is a diphenylarene-stabilized species [(η(6)-C6H5Me)Fe(I)Ph2](-) exhibiting an idealized C2v topology. This enlightens the nature of the lowest valence states accommodated by iron during the reduction of Fe(III) and Fe(II) salts by aryl Grignard reagents in the absence of any additional coligand, which so far remained rather unknown. The reactivity of these low-valent Fe(I) and Fe(0) complexes in aryl-heteroaryl Kumada cross-coupling conditions has also been investigated, and it is shown that the zerovalent Fe(0) species can be used efficiently as a precursor in this reaction, whereas the Fe(I) oxidation state does not exhibit any reactivity.
    Mots-clés : B3S, LSOD.

  • C. Corbinais, A. Mathieu, P. P. Damke, T. Kortulewski, D. Busso, M. Prado-Acosta, J. P. Radicella, et S. Marsin, « ComB proteins expression levels determine Helicobacter pylori competence capacity », Scientific Reports, vol. 7, p. 41495, janv. 2017.
    Résumé : Helicobacter pylori chronically colonises half of the world's human population and is the main cause of ulcers and gastric cancers. Its prevalence and the increase in antibiotic resistance observed recently reflect the high genetic adaptability of this pathogen. Together with high mutation rates and an efficient DNA recombination system, horizontal gene transfer through natural competence makes of H. pylori one of the most genetically diverse bacteria. We show here that transformation capacity is enhanced in strains defective for recN, extending previous work with other homologous recombination genes. However, inactivation of either mutY or polA has no effect on DNA transformation, suggesting that natural competence can be boosted in H. pylori by the persistence of DNA breaks but not by enhanced mutagenesis. The transformation efficiency of the different DNA repair impaired strains correlates with the number of transforming DNA foci formed on the cell surface and with the expression of comB8 and comB10 competence genes. Overexpression of the comB6-B10 operon is sufficient to increase the transformation capacity of a wild type strain, indicating that the ComB complex, present in the bacterial wall and essential for DNA uptake, can be a limiting factor for transformation efficiency.
    Mots-clés : B3S, FAAM.

  • P. Cuniasse, P. Tavares, E. V. Orlova, et S. Zinn-Justin, « Structures of biomolecular complexes by combination of NMR and cryoEM methods », Current Opinion in Structural Biology, vol. 43, p. 104-113, 2017.

  • L. Dhers, N. Pietrancosta, L. Ducassou, B. Ramassamy, J. Dairou, M. Jaouen, F. André, D. Mansuy, et J. - L. Boucher, « Spectral and 3D model studies of the interaction of orphan human cytochrome P450 2U1 with substrates and ligands », Biochimica et Biophysica Acta (BBA) - General Subjects, vol. 1861, nᵒ 1, p. 3144-3153, 2017.

  • T. Di Meo, W. Ghattas, C. Herrero, C. Velours, P. Minard, J. - P. Mahy, R. Ricoux, et A. Urvoas, « αRep A3: A versatile artificial scaffold for metalloenzyme design », Chemistry (Weinheim an Der Bergstrasse, Germany), mai 2017.
    Résumé : αRep is a new family of artificial proteins based on a thermostable alpha-helical repeated motif. One of its members, αRep A3, forms a stable homo-dimer with a wide cleft that is able to receive metal complexes and thus appears as suitable for generating new artificial biocatalysts. Based on the crystal structure of αRep A3, two positions (F119 and Y26) were chosen and changed independently into cysteine residues. A phenanthroline ligand was covalently attached to the unique cysteine of each protein variant and the corresponding biohybrids were purified and characterized. Once mutated and coupled to phenanthroline, the protein remained folded and dimeric. Copper(II) was bound specifically by the two biohybrids with two different binding modes and, in addition, the holo biohybrid A3F119NPH was found to be able to catalyze enantioselectively the Diels-Alder (D-A) cycloaddition with up to 62% ee. This study validates the choice of the αRep A3 dimer as a protein scaffold and provides a new promising route for the design and production of new enantioselective biohybrids based on entirely artificial proteins issued from a highly diverse library.
    Mots-clés : artificial repeat proteins, B3S, Diels-Alder reaction, Enantioselective Catalysis, MIP, PF, PIM.

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