Title: Structure and Function of TRPV channels The long-term objective of this research program is to understand the molecular mechanisms of gating and cellular function of the two physiologically important members of the TRPV subfamily: transient receptor potential vanilloid 2 (TRPV2) and transient receptor potential vanilloid 5 (TRPV5). These channels belong to the same subfamily of TRP channels, nevertheless they exhibit striking differences in their tissue distribution, physiological function, cellular localization, ion permeation and selectivity, mechanisms of channel gating and pharmacology. TRPV2 is broadly expressed Ca2+-permeable non-selective cation channel, which plays a vital role in neuronal development, immunity, cardiovascular physiology, and cancer. TRPV5 is a highly selective Ca2+ channel, that is only expressed on the apical membrane of kidney distal convoluted tubule epithelial cells and plays a critical role in Ca2+ homeostasis in the human body. This proposal is built on the major advances achieved by my group in understanding TRPV2 and TRPV5 channels structures, molecular details of gating and cellular function in the last 10 years. The overall goal of this proposal is to further understand how TRPV2 and TRPV5 channels are gated by endogenous and exogenous modulators at the atomic level; and to elucidate TRPV2 channel precise molecular function in neuronal development and immunity. To answer these questions, we will employ cutting- edge multidisciplinary approaches available to our laboratory, including membrane protein biochemistry and biophysics, single-particle cryo-EM, peroxidase-catalyzed proximity labeling and mass spectrometry, cryoAPEX for electron microscopy imaging, flow cytometry, confocal fluorescence microscopy, and functional characterization by electrophysiological and cell biological methods. This information would be critical in our understanding of TRPV channels physiological and pathophysiological roles.