8i5g
Structure of human Nav1.7 in complex with PF-05089771
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 are targeted by a number of widely used and investigational drugs for the treatment of epilepsy, arrhythmia, pain, and other disorders. Despite recent advances in structural elucidation of Na(v) channels, the binding mode of most Na(v)-targeting drugs remains unknown. Here we report high-resolution cryo-EM structures of human Na(v)1.7 treated with drugs and lead compounds with representative chemical backbones at resolutions of 2.6-3.2 A. A binding site beneath the intracellular gate (site BIG) accommodates carbamazepine, bupivacaine, and lacosamide. Unexpectedly, a second molecule of lacosamide plugs into the selectivity filter from the central cavity. Fenestrations are popular sites for various state-dependent drugs. We show that vinpocetine, a synthetic derivative of a vinca alkaloid, and hardwickiic acid, a natural product with antinociceptive effect, bind to the III-IV fenestration, while vixotrigine, an analgesic candidate, penetrates the IV-I fenestration of the pore domain. Our results permit building a 3D structural map for known drug-binding sites on Na(v) channels summarized from the present and previous structures. Structural mapping of Na(v)1.7 antagonists.,Wu Q, Huang J, Fan X, Wang K, Jin X, Huang G, Li J, Pan X, Yan N Nat Commun. 2023 Jun 3;14(1):3224. doi: 10.1038/s41467-023-38942-3. PMID:37270609[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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