Structural mechanism of heat-induced opening of a temperature-sensitive TRP channel

Nat Struct Mol Biol. 2021 Jul;28(7):564-572. doi: 10.1038/s41594-021-00615-4. Epub 2021 Jul 8.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Line
  • Cold Temperature
  • Cryoelectron Microscopy
  • HEK293 Cells
  • Hot Temperature
  • Humans
  • Ion Channel Gating
  • Lipids / chemistry
  • Mice
  • Protein Binding / physiology
  • Protein Conformation
  • TRPV Cation Channels / metabolism*
  • Thermodynamics
  • Thermosensing / physiology*


  • Lipids
  • TRPV Cation Channels
  • Trpv3 protein, mouse