8i5x | pdb_00008i5x

Structure of human Nav1.7 in complex with Vinpocetine

spinqualitylabelsall models 8i5x, resolution 2.90Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8i5x is a 3 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 2.9Å Ligands: 9Z9, LPE, NAG, P5S, PCW, T7F, Y01 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease SCN9A_HUMAN Channelopathy-associated congenital insensitivity to pain;Dravet syndrome;Primary erythromelalgia;Sodium channelopathy-related small fiber neuropathy;Generalized epilepsy with febrile seizures-plus;Hereditary sensory and autonomic neuropathy type 2;Paroxysmal extreme pain disorder;Erythromelalgia. 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. 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. The disease is caused by mutations affecting the gene represented in this entry. Function SCN9A_HUMAN Mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na(+) ions may pass in accordance with their electrochemical gradient (PubMed:7720699, PubMed:17167479, PubMed:25240195, PubMed:26680203, PubMed:15385606, PubMed:16988069, PubMed:17145499, PubMed:19369487, PubMed:24311784). It is a tetrodotoxin-sensitive Na(+) channel isoform (PubMed:7720699). Plays a role in pain mechanisms, especially in the development of inflammatory pain (PubMed:17167479, PubMed:17145499, PubMed:19369487, PubMed:24311784). Publication Abstract from PubMed Voltage-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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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