7n0m
Inactivated state of 2-APB-bound wildtype rat TRPV2 in nanodiscsInactivated state of 2-APB-bound wildtype rat TRPV2 in nanodiscs
Structural highlights
Function[TRPV2_RAT] Calcium-permeable, non-selective cation channel with an outward rectification. Seems to be regulated, at least in part, by growth factors, like IGF1, PDGF and morphogenetic neuropeptide/head activator. May transduce physical stimuli in mast cells. Activated by temperatures higher than 52 degrees Celsius; is not activated by vanilloids and acidic pH (By similarity).[1] [2] Publication Abstract from PubMedTransient receptor potential vanilloid 2 (TRPV2) is involved in many critical physiological and pathophysiological processes, making it a promising drug target. Here we present cryo-electron microscopy (cryo-EM) structures of rat TRPV2 in lipid nanodiscs activated by 2-aminoethoxydiphenyl borate (2-APB) and propose a TRPV2-specific 2-ABP binding site at the interface of S5 of one monomer and the S4-S5 linker of the adjacent monomer. In silico docking and electrophysiological studies confirm the key role of His521 and Arg539 in 2-APB activation of TRPV2. Additionally, electrophysiological experiments show that the combination of 2-APB and cannabidiol has a synergetic effect on TRPV2 activation, and cryo-EM structures demonstrate that both drugs were able to bind simultaneously. Together, our cryo-EM structures represent multiple functional states of the channel, providing a native picture of TRPV2 activation by small molecules and a structural framework for the development of TRPV2-specific activators. Structural insights into TRPV2 activation by small molecules.,Pumroy RA, Protopopova AD, Fricke TC, Lange IU, Haug FM, Nguyen PT, Gallo PN, Sousa BB, Bernardes GJL, Yarov-Yarovoy V, Leffler A, Moiseenkova-Bell VY Nat Commun. 2022 Apr 28;13(1):2334. doi: 10.1038/s41467-022-30083-3. PMID:35484159[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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