Structural snapshots of TRPV1 reveal mechanism of polymodal functionality

• Published in: Cell Vol. 184; no. 20; pp. 5138 - 5150.e12
• Main Authors: Zhang, Kaihua, Julius, David, Cheng, Yifan
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 30.09.2021
• Subjects: Allosteric Regulation; Cell Membrane Permeability - drug effects; cryo-electron microscopy; cryo-EM structure; Cryoelectron Microscopy; Diterpenes - pharmacology; HEK293 Cells; Humans; ion channel; Ion Channel Gating; ion pore permeability; ligands; Lipids - chemistry; Meglumine - pharmacology; Models, Molecular; peptides; permeability; plasticity; Protein Binding; Protein Conformation; Protons; transient receptor potential vanilloid channels; TRP channel; TRP channel gating; TRP channel polymodality; TRPV Cation Channels - agonists; TRPV Cation Channels - chemistry; TRPV Cation Channels - metabolism; TRPV1; TRP channel gating; TRP channel polymodality; TRP channel; ion channel; cryo-EM structure; TRPV1; ion pore permeability
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2021.08.012

Many transient receptor potential (TRP) channels respond to diverse stimuli and conditionally conduct small and large cations. Such functional plasticity is presumably enabled by a uniquely dynamic ion selectivity filter that is regulated by physiological agents. What is currently missing is a “photo series” of intermediate structural states that directly address this hypothesis and reveal specific mechanisms behind such dynamic channel regulation. Here, we exploit cryoelectron microscopy (cryo-EM) to visualize conformational transitions of the capsaicin receptor, TRPV1, as a model to understand how dynamic transitions of the selectivity filter in response to algogenic agents, including protons, vanilloid agonists, and peptide toxins, permit permeation by small and large organic cations. These structures also reveal mechanisms governing ligand binding substates, as well as allosteric coupling between key sites that are proximal to the selectivity filter and cytoplasmic gate. These insights suggest a general framework for understanding how TRP channels function as polymodal signal integrators. [Display omitted] •Transitional TRPV1 substates reveal two-step mechanism of proton modulation•Substates reveal PI lipid and vanilloid agonist binding stoichiometry and competition•Adaptive selectivity filter accommodates permeation by small and large organic cations•Conformational snapshots reveal allosteric mechanisms connecting key regulatory sites Visualizing substates of the TRPV1 channel reveals mechanisms underlying selectivity filter plasticity, ligand binding, and allosteric coupling.