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Cis–trans isomerization at a proline opens the pore of a neurotransmitter-gated ion channel

Lummis, Sarah C. R. and Beene, Darren L. and Lee, Lori W. and Lester, Henry A. and Broadhurst, R. William and Dougherty, Dennis A. (2005) Cis–trans isomerization at a proline opens the pore of a neurotransmitter-gated ion channel. Nature, 438 (4065). pp. 248-252. ISSN 0028-0836. https://resolver.caltech.edu/CaltechAUTHORS:20150319-085128410

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Abstract

5-Hydroxytryptamine type 3 (5-HT_3) receptors are members of the Cys-loop receptor superfamily. Neurotransmitter binding in these proteins triggers the opening (gating) of an ion channel by means of an as-yet-uncharacterized conformational change. Here we show that a specific proline (Pro 8*), located at the apex of the loop between the second and third transmembrane helices (M2–M3), can link binding to gating through a cis–trans isomerization of the protein backbone. Using unnatural amino acid mutagenesis, a series of proline analogues with varying preference for the cis conformer was incorporated at the 8* position. Proline analogues that strongly favour the trans conformer produced non-functional channels. Among the functional mutants there was a strong correlation between the intrinsic cis–trans energy gap of the proline analogue and the activation of the channel, suggesting that cis–trans isomerization of this single proline provides the switch that interconverts the open and closed states of the channel. Consistent with this proposal, nuclear magnetic resonance studies on an M2–M3 loop peptide reveal two distinct, structured forms. Our results thus confirm the structure of the M2–M3 loop and the critical role of Pro 8* in the 5-HT_3 receptor. In addition, they suggest that a molecular rearrangement at Pro 8* is the structural mechanism that opens the receptor pore.


Item Type:Article
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http://dx.doi.org/10.1038/nature04130DOIArticle
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ORCID:
AuthorORCID
Lummis, Sarah C. R.0000-0001-9410-9805
Lester, Henry A.0000-0002-5470-5255
Dougherty, Dennis A.0000-0003-1464-2461
Additional Information:© 2005 Nature Publishing Group. Received 24 March; accepted 8 August 2005. S.C.R.L. is a Wellcome Trust Senior Research Fellow in Basic Biomedical Science. The work at Caltech was supported by the National Institutes of Health. We thank K. L. Price and A. J. Thompson for assistance with modelling.
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Funding AgencyGrant Number
Wellcome TrustUNSPECIFIED
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Issue or Number:4065
Record Number:CaltechAUTHORS:20150319-085128410
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20150319-085128410
Official Citation:Lummis, S. C. R., Beene, D. L., Lee, L. W., Lester, H. A., Broadhurst, R. W., & Dougherty, D. A. (2005). Cis-trans isomerization at a proline opens the pore of a neurotransmitter-gated ion channel. [10.1038/nature04130]. Nature, 438(7065), 248-252.
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:55917
Collection:CaltechAUTHORS
Deposited By: Jason Perez
Deposited On:24 Mar 2015 22:15
Last Modified:16 Apr 2020 23:36

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