XB-ART-54633
Nat Struct Mol Biol
2018 Mar 01;253:252-260. doi: 10.1038/s41594-018-0037-5.
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Cryo-EM and X-ray structures of TRPV4 reveal insight into ion permeation and gating mechanisms.
Deng Z
,
Paknejad N
,
Maksaev G
,
Sala-Rabanal M
,
Nichols CG
,
Hite RK
,
Yuan P
.
???displayArticle.abstract???
The transient receptor potential (TRP) channel TRPV4 participates in multiple biological processes, and numerous TRPV4 mutations underlie several distinct and devastating diseases. Here we present the cryo-EM structure of Xenopus tropicalis TRPV4 at 3.8-Å resolution. The ion-conduction pore contains an intracellular gate formed by the inner helices, but lacks any extracellular gate in the selectivity filter, as observed in other TRPV channels. Anomalous X-ray diffraction analyses identify a single ion-binding site in the selectivity filter, thus explaining TRPV4 nonselectivity. Structural comparisons with other TRP channels and distantly related voltage-gated cation channels reveal an unprecedented, unique packing interface between the voltage-sensor-like domain and the pore domain, suggesting distinct gating mechanisms. Moreover, our structure begins to provide mechanistic insights to the large set of pathogenic mutations, offering potential opportunities for drug development.
???displayArticle.pubmedLink??? 29483651
???displayArticle.pmcLink??? PMC6252174
???displayArticle.link??? Nat Struct Mol Biol
???displayArticle.grants??? [+]
P30 CA008748 NCI NIH HHS , S10 RR029205 NCRR NIH HHS , R01 NS099341 NINDS NIH HHS , P41 GM103403 NIGMS NIH HHS , S10 OD021527 NIH HHS , R35 HL140024 NHLBI NIH HHS , 17SDG33400229 American Heart Association-American Stroke Association
Species referenced: Xenopus tropicalis
Genes referenced: trpv4
GO keywords: voltage-gated cation channel activity [+]
???displayArticle.omims??? BRACHYOLMIA TYPE 3; BCYM3 [+]
METATROPIC DYSPLASIA; MTD
PARASTREMMATIC DWARFISM
SCAPULOPERONEAL SPINAL MUSCULAR ATROPHY; SPSMA
SPONDYLOEPIPHYSEAL DYSPLASIA, MAROTEAUX TYPE
HEREDITARY MOTOR AND SENSORY NEUROPATHY, TYPE IIC; HMSN2C
DIGITAL ARTHROPATHY-BRACHYDACTYLY, FAMILIAL; FDAB
SODIUM SERUM LEVEL QUANTITATIVE TRAIT LOCUS 1; SSQTL1
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