7xm9

Cryo-EM structure of human NaV1.7/beta1/beta2-XEN907

spinqualitylabelsall models 7xm9, resolution 3.22Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7xm9 is a 3 chain structure with sequence from Aequorea victoria and Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.22Å Ligands: 6OU, G2E, NAG 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 channel Na(V)1.7 plays essential roles in pain and odor perception. Na(V)1.7 variants cause pain disorders. Accordingly, Na(V)1.7 has elicited extensive attention in developing new analgesics. Here we present cryo-EM structures of human Na(V)1.7/beta1/beta2 complexed with inhibitors XEN907, TC-N1752 and Na(V)1.7-IN2, explaining specific binding sites and modulation mechanism for the pore blockers. These inhibitors bind in the central cavity blocking ion permeation, but engage different parts of the cavity wall. XEN907 directly causes alpha- to pi-helix transition of DIV-S6 helix, which tightens the fast inactivation gate. TC-N1752 induces pi-helix transition of DII-S6 helix mediated by a conserved asparagine on DIII-S6, which closes the activation gate. Na(V)1.7-IN2 serves as a pore blocker without causing conformational change. Electrophysiological results demonstrate that XEN907 and TC-N1752 stabilize Na(V)1.7 in inactivated state and delay the recovery from inactivation. Our results provide structural framework for Na(V)1.7 modulation by pore blockers, and important implications for developing subtype-selective analgesics. Structural basis for Na(V)1.7 inhibition by pore blockers.,Zhang J, Shi Y, Huang Z, Li Y, Yang B, Gong J, Jiang D Nat Struct Mol Biol. 2022 Dec;29(12):1208-1216. doi: 10.1038/s41594-022-00860-1. , Epub 2022 Nov 24. PMID:36424527 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Ion channels 3D structures

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