Numerous physiological functions rely on distinguishing temperature through temperature-sensitive transient receptor potential channels (thermo-TRPs). Although the function of thermo-TRPs has been studied extensively, structural determination of their heat- and cold-activated states has remained a challenge. Here, we present cryo-EM structures of the nanodisc-reconstituted wild-type mouse TRPV3 in three distinct conformations: closed, heat-activated sensitized and open states. The heat-induced transformations of TRPV3 are accompanied by changes in the secondary structure of the S2-S3 linker and the N and C termini and represent a conformational wave that links these parts of the protein to a lipid occupying the vanilloid binding site. State-dependent differences in the behavior of bound lipids suggest their active role in thermo-TRP temperature-dependent gating. Our structural data, supported by physiological recordings and molecular dynamics simulations, provide an insight for understanding the molecular mechanism of temperature sensing.

Department of Biochemistry and Molecular Biophysics Columbia University New York NY USA

Department of Cancer Biology and Pharmacology University of Illinois College of Medicine Peoria IL USA

Department of Cellular Neurophysiology Institute of Physiology Czech Academy of Sciences Prague Czech Republic

National Research Nuclear University Moscow Engineering Physics Institute Moscow Russia

National Research University Higher School of Economics Moscow Russia

Research Center for Molecular Mechanisms of Aging and Age related Diseases Moscow Institute of Physics and Technology Dolgoprudny Moscow Russia

Shemyakin Ovchinnikov Institute of Bioorganic Chemistry Russian Academy of Sciences Moscow Russia

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Human Transient Receptor Potential Ankyrin 1 Channel: Structure, Function, and Physiology

Cannabinoid non-cannabidiol site modulation of TRPV2 structure and function

The human TRPA1 intrinsic cold and heat sensitivity involves separate channel structures beyond the N-ARD domain