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Unwinding and spiral sliding of S4 and domain rotation of VSD during the electromechanical coupling in Nav1.7.

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Huang G, Wu Q, Li Z, Jin X, Huang X, Wu T, Pan X, Yan N
OpenAccess logo Proc Natl Acad Sci U S A 119 e2209164119 (2022)
Cited: 23 times
EuropePMC logo PMID: 35878056

Abstract

Voltage-gated sodium (Nav) channel Nav1.7 has been targeted for the development of nonaddictive pain killers. Structures of Nav1.7 in distinct functional states will offer an advanced mechanistic understanding and aid drug discovery. Here we report the cryoelectron microscopy analysis of a human Nav1.7 variant that, with 11 rationally introduced point mutations, has a markedly right-shifted activation voltage curve with V1/2 reaching 69 mV. The voltage-sensing domain in the first repeat (VSDI) in a 2.7-Å resolution structure displays a completely down (deactivated) conformation. Compared to the structure of WT Nav1.7, three gating charge (GC) residues in VSDI are transferred to the cytosolic side through a combination of helix unwinding and spiral sliding of S4I and ∼20° domain rotation. A conserved WNФФD motif on the cytoplasmic end of S3I stabilizes the down conformation of VSDI. One GC residue is transferred in VSDII mainly through helix sliding. Accompanying GC transfer in VSDI and VSDII, rearrangement and contraction of the intracellular gate is achieved through concerted movements of adjacent segments, including S4-5I, S4-5II, S5II, and all S6 segments. Our studies provide important insight into the electromechanical coupling mechanism of the single-chain voltage-gated ion channels and afford molecular interpretations for a number of pain-associated mutations whose pathogenic mechanism cannot be revealed from previously reported Nav structures.

Articles - 7xvf mentioned but not cited (3)

  1. A mechanistic reinterpretation of fast inactivation in voltage-gated Na+ channels. Liu Y, Bassetto CAZ, Pinto BI, Bezanilla F. Nat Commun 14 5072 (2023)
  2. research-article A Mechanistic Reinterpretation of Fast Inactivation in Voltage-Gated Na + Channels. Liu Y, Bassetto CAZ, Pinto BI, Bezanilla F. bioRxiv 2023.04.27.538555 (2023)
  3. research-article A Mechanistic Reinterpretation of Fast Inactivation in Voltage-Gated Na+ Channels. Liu Y, Bassetto CAZ, Pinto BI, Bezanilla F. Res Sq rs.3.rs-2924505 (2023)


Reviews citing this publication (3)

  1. A structural atlas of druggable sites on Nav channels. Li Z, Wu Q, Yan N. Channels (Austin) 18 2287832 (2024)
  2. Pathology of pain and its implications for therapeutic interventions. Cao B, Xu Q, Shi Y, Zhao R, Li H, Zheng J, Liu F, Wan Y, Wei B. Signal Transduct Target Ther 9 155 (2024)
  3. Structural biology and molecular pharmacology of voltage-gated ion channels. Huang J, Pan X, Yan N. Nat Rev Mol Cell Biol (2024)

Articles citing this publication (17)



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