Vanilloid-dependent TRPV1 opening trajectory from cryoEM ensemble analysis

• Published in: Nature communications Vol. 13; no. 1; p. 2874
• Main Authors: Kwon, Do Hoon, Zhang, Feng, Fedor, Justin G., Suo, Yang, Lee, Seok-Yong
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24-05-2022; Nature Publishing Group; Nature Portfolio
• Subjects: 101/28; 631/45/269/1153; 631/535/1258/1259; 631/57/2283; 9/74; Arthritis; BASIC BIOLOGICAL SCIENCES; Binding sites; Biochemical Phenomena; Capsaicin receptors; Cryoelectron Microscopy; Datasets; Diterpenes - pharmacology; Heat; Humanities and Social Sciences; Ligands; multidisciplinary; Pain; permeation and transport; Protein Conformation; Proteins; Resiniferatoxin; Science; Science (multidisciplinary); Selectivity; Temporal resolution; Titration; Trajectory analysis; transient receptor potential channels; TRPV Cation Channels - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-30602-2

Single particle cryo-EM often yields multiple protein conformations within a single dataset, but experimentally deducing the temporal relationship of these conformers within a conformational trajectory is not trivial. Here, we use thermal titration methods and cryo-EM in an attempt to obtain temporal resolution of the conformational trajectory of the vanilloid receptor TRPV1 with resiniferatoxin (RTx) bound. Based on our cryo-EM ensemble analysis, RTx binding to TRPV1 appears to induce intracellular gate opening first, followed by selectivity filter dilation, then pore loop rearrangement to reach the final open state. This apparent conformational wave likely arises from the concerted, stepwise, additive structural changes of TRPV1 over many subdomains. Greater understanding of the RTx-mediated long-range allostery of TRPV1 could help further the therapeutic potential of RTx, which is a promising drug candidate for pain relief associated with advanced cancer or knee arthritis.
Cryo-EM often yields multiple protein conformations within a single dataset. Using the thermal titration methods and cryo-EM, Do Hoon Kwon et al. elucidate the conformational trajectory of the TRPV1 with resiniferatoxin (RTx) bound.