7WFR

Human Nav1.8 with A-803467, class III

Summary for 7WFR

• Entry DOI: 10.2210/pdb7wfr/pdb
• EMDB information: 32475
• Descriptor: Sodium channel protein type 10 subunit alpha, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (8 entities in total)
• Functional Keywords: voltage-gated sodium channel, nav, activation, selectivity, membrane protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 237137.40

Authors

Yan, N.,Pan, X.J.,Huang, X.S.,Huang, G.X. (deposition date: 2021-12-27, release date: 2022-08-03, Last modification date: 2022-09-21)

Primary citation

Huang, X.,Jin, X.,Huang, G.,Huang, J.,Wu, T.,Li, Z.,Chen, J.,Kong, F.,Pan, X.,Yan, N.
Structural basis for high-voltage activation and subtype-specific inhibition of human Na v 1.8.
Proc.Natl.Acad.Sci.USA, 119:e2208211119-e2208211119, 2022

PubMed Abstract: The dorsal root ganglia-localized voltage-gated sodium (Na) channel Na1.8 represents a promising target for developing next-generation analgesics. A prominent characteristic of Na1.8 is the requirement of more depolarized membrane potential for activation. Here we present the cryogenic electron microscopy structures of human Na1.8 alone and bound to a selective pore blocker, A-803467, at overall resolutions of 2.7 to 3.2 Å. The first voltage-sensing domain (VSD) displays three different conformations. Structure-guided mutagenesis identified the extracellular interface between VSD 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. Our structure-guided functional characterizations show that two nonligand binding residues, Thr397 on S6 and Gly1406 on S6, allosterically modulate the channel's sensitivity to A-803467. Comparison of available structures of human Na channels suggests the extracellular loop region to be a potential site for developing subtype-specific pore-blocking biologics.

PubMed: 35858452
DOI: 10.1073/pnas.2208211119

Experimental method

ELECTRON MICROSCOPY (3 Å)