7xve | pdb_00007xve

Human Nav1.7 mutant class-I

spinqualitylabelsall models 7xve, resolution 2.70Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7xve 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 2.7Å Ligands: 1PW, CLR, LPE, NAG, P5S, PCW, 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)) channel Na(v)1.7 has been targeted for the development of nonaddictive pain killers. Structures of Na(v)1.7 in distinct functional states will offer an advanced mechanistic understanding and aid drug discovery. Here we report the cryoelectron microscopy analysis of a human Na(v)1.7 variant that, with 11 rationally introduced point mutations, has a markedly right-shifted activation voltage curve with V(1/2) reaching 69 mV. The voltage-sensing domain in the first repeat (VSD(I)) in a 2.7-A resolution structure displays a completely down (deactivated) conformation. Compared to the structure of WT Na(v)1.7, three gating charge (GC) residues in VSD(I) are transferred to the cytosolic side through a combination of helix unwinding and spiral sliding of S4(I) and approximately 20 degrees domain rotation. A conserved WNcapital EF, Cyrilliccapital EF, CyrillicD motif on the cytoplasmic end of S3(I) stabilizes the down conformation of VSD(I). One GC residue is transferred in VSD(II) mainly through helix sliding. Accompanying GC transfer in VSD(I) and VSD(II), rearrangement and contraction of the intracellular gate is achieved through concerted movements of adjacent segments, including S4-5(I), S4-5(II), S5(II), and all S6 segments. Our studies provide important insight into the electromechanical coupling mechanism of the single-chain voltage-gated ion channels and afford molecular interpretations for a number of pain-associated mutations whose pathogenic mechanism cannot be revealed from previously reported Na(v) structures. Unwinding and spiral sliding of S4 and domain rotation of VSD during the electromechanical coupling in Na(v)1.7.,Huang G, Wu Q, Li Z, Jin X, Huang X, Wu T, Pan X, Yan N Proc Natl Acad Sci U S A. 2022 Aug 16;119(33):e2209164119. doi: , 10.1073/pnas.2209164119. Epub 2022 Jul 25. PMID:35878056 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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