8gz2
Cryo-EM structure of human NaV1.6/beta1/beta2-4,9-anhydro-tetrodotoxin
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 PubMedThe sodium channel Na(V)1.6 is widely expressed in neurons of the central and peripheral nervous systems, which plays a critical role in regulating neuronal excitability. Dysfunction of Na(V)1.6 has been linked to epileptic encephalopathy, intellectual disability and movement disorders. Here we present cryo-EM structures of human Na(V)1.6/beta1/beta2 alone and complexed with a guanidinium neurotoxin 4,9-anhydro-tetrodotoxin (4,9-ah-TTX), revealing molecular mechanism of Na(V)1.6 inhibition by the blocker. The apo-form structure reveals two potential Na(+) binding sites within the selectivity filter, suggesting a possible mechanism for Na(+) selectivity and conductance. In the 4,9-ah-TTX bound structure, 4,9-ah-TTX binds to a pocket similar to the tetrodotoxin (TTX) binding site, which occupies the Na(+) binding sites and completely blocks the channel. Molecular dynamics simulation results show that subtle conformational differences in the selectivity filter affect the affinity of TTX analogues. Taken together, our results provide important insights into Na(V)1.6 structure, ion conductance, and inhibition. Structure of human Na(V)1.6 channel reveals Na(+) selectivity and pore blockade by 4,9-anhydro-tetrodotoxin.,Li Y, Yuan T, Huang B, Zhou F, Peng C, Li X, Qiu Y, Yang B, Zhao Y, Huang Z, Jiang D Nat Commun. 2023 Feb 23;14(1):1030. doi: 10.1038/s41467-023-36766-9. PMID:36823201[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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