NYS, Mieke, Eveline WIJCKMANS, Ana FARINHA, Ozge YOLUK, Magnus ANDERSSON, Marijke BRAMS, Radovan SPURNÝ, Steve PEIGNEUR, Jan TYTGAT, Erik LINDAHL and Chris ULENS. Allosteric binding site in a Cys-loop receptor ligand-binding domain unveiled in the crystal structure of ELIC in complex with chlorpromazine. Proceedings of the National Academy of Sciences of the United States of America. WASHINGTON: National Academy of Sciences, 2016, vol. 113, No 43, p. "E6696"-"E6703", 8 pp. ISSN 0027-8424. Available from: https://dx.doi.org/10.1073/pnas.1603101113. |
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@article{1375144, author = {Nys, Mieke and Wijckmans, Eveline and Farinha, Ana and Yoluk, Ozge and Andersson, Magnus and Brams, Marijke and Spurný, Radovan and Peigneur, Steve and Tytgat, Jan and Lindahl, Erik and Ulens, Chris}, article_location = {WASHINGTON}, article_number = {43}, doi = {http://dx.doi.org/10.1073/pnas.1603101113}, keywords = {ligand-gated ion channel; X-ray crystallography; allosteric modulation; Cys-loop receptor; nicotinic acetylcholine receptor}, language = {eng}, issn = {0027-8424}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, title = {Allosteric binding site in a Cys-loop receptor ligand-binding domain unveiled in the crystal structure of ELIC in complex with chlorpromazine}, url = {http://www.pnas.org/content/113/43/E6696}, volume = {113}, year = {2016} }
TY - JOUR ID - 1375144 AU - Nys, Mieke - Wijckmans, Eveline - Farinha, Ana - Yoluk, Ozge - Andersson, Magnus - Brams, Marijke - Spurný, Radovan - Peigneur, Steve - Tytgat, Jan - Lindahl, Erik - Ulens, Chris PY - 2016 TI - Allosteric binding site in a Cys-loop receptor ligand-binding domain unveiled in the crystal structure of ELIC in complex with chlorpromazine JF - Proceedings of the National Academy of Sciences of the United States of America VL - 113 IS - 43 SP - "E6696"-"E6703" EP - "E6696"-"E6703" PB - National Academy of Sciences SN - 00278424 KW - ligand-gated ion channel KW - X-ray crystallography KW - allosteric modulation KW - Cys-loop receptor KW - nicotinic acetylcholine receptor UR - http://www.pnas.org/content/113/43/E6696 L2 - http://www.pnas.org/content/113/43/E6696 N2 - Pentameric ligand-gated ion channels or Cys-loop receptors are responsible for fast inhibitory or excitatory synaptic transmission. The antipsychotic compound chlorpromazine is a widely used tool to probe the ion channel pore of the nicotinic acetylcholine receptor, which is a prototypical Cys-loop receptor. In this study, we determine the molecular determinants of chlorpromazine binding in the Erwinia ligand-gated ion channel (ELIC). We report the X-ray crystal structures of ELIC in complex with chlorpromazine or its brominated derivative bromopromazine. Unexpectedly, we do not find a chlorpromazine molecule in the channel pore of ELIC, but behind the beta 8-beta 9 loop in the extracellular ligand-binding domain. The beta 8-beta 9 loop is localized downstream from the neurotransmitter binding site and plays an important role in coupling of ligand binding to channel opening. In combination with electrophysiological recordings from ELIC cysteine mutants and a thiol-reactive derivative of chlorpromazine, we demonstrate that chlorpromazine binding at the beta 8-beta 9 loop is responsible for receptor inhibition. We further use molecular-dynamics simulations to support the X-ray data and mutagenesis experiments. Together, these data unveil an allosteric binding site in the extracellular ligand-binding domain of ELIC. Our results extend on previous observations and further substantiate our understanding of a multisite model for allosteric modulation of Cys-loop receptors. ER -
NYS, Mieke, Eveline WIJCKMANS, Ana FARINHA, Ozge YOLUK, Magnus ANDERSSON, Marijke BRAMS, Radovan SPURNÝ, Steve PEIGNEUR, Jan TYTGAT, Erik LINDAHL and Chris ULENS. Allosteric binding site in a Cys-loop receptor ligand-binding domain unveiled in the crystal structure of ELIC in complex with chlorpromazine. \textit{Proceedings of the National Academy of Sciences of the United States of America}. WASHINGTON: National Academy of Sciences, 2016, vol.~113, No~43, p.~''E6696''-''E6703'', 8 pp. ISSN~0027-8424. Available from: https://dx.doi.org/10.1073/pnas.1603101113.
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