7w77
cryo-EM structure of human NaV1.3/beta1/beta2-bulleyaconitineA
Structural highlights
DiseaseSCN1B_HUMAN Dravet syndrome;Familial progressive cardiac conduction defect;Generalized epilepsy with febrile seizures-plus;Brugada syndrome. The disease is caused by mutations affecting the gene represented in this entry. The gene represented in this entry may be involved in disease pathogenesis. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. FunctionSCN1B_HUMAN Crucial in the assembly, expression, and functional modulation of the heterotrimeric complex of the sodium channel. The subunit beta-1 can modulate multiple alpha subunit isoforms from brain, skeletal muscle, and heart. Its association with NFASC may target the sodium channels to the nodes of Ranvier of developing axons and retain these channels at the nodes in mature myelinated axons.[1] Isoform 2: Cell adhesion molecule that plays a critical role in neuronal migration and pathfinding during brain development. Stimulates neurite outgrowth.[2] Publication Abstract from PubMedVoltage-gated sodium (Na(V)) channels play fundamental roles in initiating and propagating action potentials. Na(V)1.3 is involved in numerous physiological processes including neuronal development, hormone secretion and pain perception. Here we report structures of human Na(V)1.3/beta1/beta2 in complex with clinically-used drug bulleyaconitine A and selective antagonist ICA121431. Bulleyaconitine A is located around domain I-II fenestration, providing the detailed view of the site-2 neurotoxin binding site. It partially blocks ion path and expands the pore-lining helices, elucidating how the bulleyaconitine A reduces peak amplitude but improves channel open probability. In contrast, ICA121431 preferentially binds to activated domain IV voltage-sensor, consequently strengthens the Ile-Phe-Met motif binding to its receptor site, stabilizes the channel in inactivated state, revealing an allosterically inhibitory mechanism of Na(V) channels. Our results provide structural details of distinct small-molecular modulators binding sites, elucidate molecular mechanisms of their action on Na(V) channels and pave a way for subtype-selective therapeutic development. Structural basis for modulation of human Na(V)1.3 by clinical drug and selective antagonist.,Li X, Xu F, Xu H, Zhang S, Gao Y, Zhang H, Dong Y, Zheng Y, Yang B, Sun J, Zhang XC, Zhao Y, Jiang D Nat Commun. 2022 Mar 11;13(1):1286. doi: 10.1038/s41467-022-28808-5. PMID:35277491[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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