7we4
From Proteopedia
Human Nav1.8 with A-803467, class I
Structural highlights
DiseaseSCNAA_HUMAN Brugada syndrome;Primary erythromelalgia;Hereditary sodium channelopathy-related small fibers neuropathy;Paroxysmal extreme pain disorder;Romano-Ward syndrome;Congenital insensitivity to pain-anosmia-neuropathic arthropathy. The disease is caused by variants affecting the gene represented in this entry. FunctionSCNAA_HUMAN Tetrodotoxin-resistant channel that mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which sodium ions may pass in accordance with their electrochemical gradient. Plays a role in neuropathic pain mechanisms.[1] [2] Publication Abstract from PubMedThe dorsal root ganglia-localized voltage-gated sodium (Na(v)) channel Na(v)1.8 represents a promising target for developing next-generation analgesics. A prominent characteristic of Na(v)1.8 is the requirement of more depolarized membrane potential for activation. Here we present the cryogenic electron microscopy structures of human Na(v)1.8 alone and bound to a selective pore blocker, A-803467, at overall resolutions of 2.7 to 3.2 A. The first voltage-sensing domain (VSD(I)) displays three different conformations. Structure-guided mutagenesis identified the extracellular interface between VSD(I) and the pore domain (PD) to be a determinant for the high-voltage dependence of activation. A-803467 was clearly resolved in the central cavity of the PD, clenching S6(IV). Our structure-guided functional characterizations show that two nonligand binding residues, Thr397 on S6(I) and Gly1406 on S6(III), allosterically modulate the channel's sensitivity to A-803467. Comparison of available structures of human Na(v) channels suggests the extracellular loop region to be a potential site for developing subtype-specific pore-blocking biologics. Structural basis for high-voltage activation and subtype-specific inhibition of human Na(v)1.8.,Huang X, Jin X, Huang G, Huang J, Wu T, Li Z, Chen J, Kong F, Pan X, Yan N Proc Natl Acad Sci U S A. 2022 Jul 26;119(30):e2208211119. doi: , 10.1073/pnas.2208211119. Epub 2022 Jul 19. PMID:35858452[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
| ||||||||||||||||||||
Categories: Homo sapiens | Large Structures | Huang GX | Huang XS | Pan XJ | Yan N
