期刊
NATURE
卷 438, 期 7065, 页码 248-252出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nature04130
关键词
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资金
- Wellcome Trust Funding Source: Medline
5-Hydroxytryptamine type 3 (5-HT3) receptors are members of the Cys-loop receptor superfamily(1). 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)(2,3), 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 nonfunctional 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-HT3 receptor. In addition, they suggest that a molecular rearrangement at Pro 8* is the structural mechanism that opens the receptor pore.
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