Department of Physiology and Membrane Biology, University of California Davis, School of Medicine, Davis, United States.
Department of Pharmacology, University of California Davis, School of Medicine, Davis, United States.
Elife. 2020 Nov 9;9:e62039. doi: 10.7554/eLife.62039.
The capsaicin receptor TRPV1 is an outstanding representative of ligand-gated ion channels in ligand selectivity and sensitivity. However, molecular interactions that stabilize the ligand-binding pocket in its permissive conformation, and how many permissive conformations the ligand-binding pocket may adopt, remain unclear. To answer these questions, we designed a pair of novel capsaicin analogs to increase or decrease the ligand size by about 1.5 Å without altering ligand chemistry. Together with capsaicin, these ligands form a set of molecular rulers for investigating ligand-induced conformational changes. Computational modeling and functional tests revealed that structurally these ligands alternate between drastically different binding poses but stabilize the ligand-binding pocket in nearly identical permissive conformations; functionally, they all yielded a stable open state despite varying potencies. Our study suggests the existence of an optimal ligand-binding pocket conformation for capsaicin-mediated TRPV1 activation gating, and reveals multiple ligand-channel interactions that stabilize this permissive conformation.
辣椒素受体 TRPV1 是配体门控离子通道在配体选择性和敏感性方面的杰出代表。然而，稳定其允许构象中配体结合口袋的分子相互作用，以及配体结合口袋可能采用的允许构象的数量，仍不清楚。为了回答这些问题，我们设计了一对新型辣椒素类似物，通过大约 1.5 Å 的大小改变来增加或减少配体的大小，而不改变配体的化学性质。与辣椒素一起，这些配体形成了一组分子标尺，用于研究配体诱导的构象变化。计算建模和功能测试表明，从结构上看，这些配体在完全不同的结合构象之间交替，但稳定配体结合口袋处于几乎相同的允许构象；从功能上看，尽管效力不同，但它们都产生了稳定的开放状态。我们的研究表明，存在一种最优的配体结合口袋构象，用于介导 TRPV1 激活门控的辣椒素，并且揭示了稳定这种允许构象的多种配体-通道相互作用。
