7w9m

Cryo-EM structure of human Nav1.7(E406K) in complex with auxiliary beta subunits, ProTx-II and tetrodotoxin (S6IV pi helix conformer)

spinqualitylabelsall models 7w9m, resolution 3.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7w9m 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 3Å Ligands: 9SR, LPE, NAG, P5S, 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 Na(v)1.7 represents a preeminent target for next-generation analgesics for its critical role in pain sensation. Here we report a 2.2-A resolution cryo-EM structure of wild-type (WT) Na(v)1.7 complexed with the beta1 and beta2 subunits that reveals several previously indiscernible cytosolic segments. Reprocessing of the cryo-EM data for our reported structures of Na(v)1.7(E406K) bound to various toxins identifies two distinct conformations of S6(IV), one composed of alpha helical turns only and the other containing a pi helical turn in the middle. The structure of ligand-free Na(v)1.7(E406K), determined at 3.5-A resolution, is identical to the WT channel, confirming that binding of Huwentoxin IV or Protoxin II to VSD(II) allosterically induces the alpha --> pi transition of S6(IV). The local secondary structural shift leads to contraction of the intracellular gate, closure of the fenestration on the interface of repeats I and IV, and rearrangement of the binding site for the fast inactivation motif. High-resolution structures of human Na(v)1.7 reveal gating modulation through alpha-pi helical transition of S6(IV).,Huang G, Liu D, Wang W, Wu Q, Chen J, Pan X, Shen H, Yan N Cell Rep. 2022 Apr 26;39(4):110735. doi: 10.1016/j.celrep.2022.110735. PMID:35476982 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Ion channels 3D structures

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