TRP channels represent a group of non-selective cation channels that respond to a wide range of chemical and physical stimuli. It is a large and diverse superfamily, second only to potassium channels. TRP Vanilloid (TRPV) is a subfamily of thermosensitive TRP channels that enable somatosensory neurons to detect changes in ambient temperature. They are expressed in sensory nerves and/or other cell types, where they play important roles in sensing environmental noxious stimuli such as high temperature, acidic pH and natural or synthetic irritants. However, despite their intriguing roles in a number of physiological and pathophysiological processes, structural studies of TRP ion channels have been very challenging. A major bottleneck has been the difficulties in obtaining well-ordered three-dimensional (3D) crystals for any member of the TRP channel superfamily, which is a prerequisite for structure determination by X-ray crystallography as the most successful and well-established method for protein structure determination. Recent technological breakthroughs in single particle electron cryomicroscopy (cryoEM) have enabled near atomic resolution structure determination of macromolecules of various sizes and symmetry, no longer limited to highly symmetrical large object. It also enabled atomic structure determination of integral membrane proteins without requiring formation of 3D crystals. We determined the atomic structure of TRPV1 ion channel, which is the first atomic structure of the entire TRP channel family and the first atomic structure of an integral membrane protein determined by single particle cryoEM. We will use near atomic resolution single particle cryoEM as our main structural analysis tool, together with other methods in molecular biology, biochemistry and biophysics, to elucidate the mechanism that governs the functions of a subfamily of TRP channels, TRPV. We will address following specific questions: (1) what is the mechanism of polymodal activation of TRPV1 ion channel, a receptor for capsaicin; (2) what is the mechanism of thermosensitivity of TRPV channels; and (3) to improve the resolution of single particle cryoEM further to visualize ligands and ions binding. Substantial completion of these aims will advance our knowledge about the TRP channel function as well as advancing the technology of single particle cryoEM.

Public Health Relevance

Transient Receptor Potential (TRP) channel superfamily contains a large diverse group of non-selective cation channels. Channel activations of members of a vanilloid subfamily, TRPV, are thermosensitive and polymodal. We aim to use single particle electron cryomicroscopy, a high-resolution structure determination method that does not require formation of three-dimensional crystals, to elucidate the mechanisms underlying the polymodal activation, including thermosensitivity, of TRPV channel.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Nie, Zhongzhen
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Francisco
Schools of Medicine
San Francisco
United States
Zip Code
Cormier, Anthony; Campbell, Melody G; Ito, Saburo et al. (2018) Cryo-EM structure of the ?v?8 integrin reveals a mechanism for stabilizing integrin extension. Nat Struct Mol Biol 25:698-704
Kintzer, Alexander F; Green, Evan M; Dominik, Pawel K et al. (2018) Structural basis for activation of voltage sensor domains in an ion channel TPC1. Proc Natl Acad Sci U S A 115:E9095-E9104
Autzen, Henriette E; Myasnikov, Alexander G; Campbell, Melody G et al. (2018) Structure of the human TRPM4 ion channel in a lipid nanodisc. Science 359:228-232
Zhang, Yunxiao; Bulkley, David P; Xin, Yao et al. (2018) Structural Basis for Cholesterol Transport-like Activity of the Hedgehog Receptor Patched. Cell 175:1352-1364.e14
Cheng, Yifan (2018) Single-particle cryo-EM-How did it get here and where will it go. Science 361:876-880
Cheng, Yifan (2018) Membrane protein structural biology in the era of single particle cryo-EM. Curr Opin Struct Biol 52:58-63
Palovcak, Eugene; Wang, Feng; Zheng, Shawn Q et al. (2018) A simple and robust procedure for preparing graphene-oxide cryo-EM grids. J Struct Biol 204:80-84
Nguyen, Nam X; Armache, Jean-Paul; Lee, Changkeun et al. (2018) Cryo-EM structure of a fungal mitochondrial calcium uniporter. Nature 559:570-574
Dang, Shangyu; Feng, Shengjie; Tien, Jason et al. (2017) Cryo-EM structures of the TMEM16A calcium-activated chloride channel. Nature 552:426-429
Jin, Peng; Bulkley, David; Guo, Yanmeng et al. (2017) Electron cryo-microscopy structure of the mechanotransduction channel NOMPC. Nature 547:118-122

Showing the most recent 10 out of 34 publications