8fhd
Cryo-EM structure of human voltage-gated sodium channel Nav1.6
Structural highlights
DiseaseSCN8A_HUMAN Non-specific early-onset epileptic encephalopathy;Infantile convulsions and choreoathetosis;Benign familial infantile epilepsy. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. The disease may be caused by variants affecting the gene represented in this entry. FunctionSCN8A_HUMAN Mediates the voltage-dependent sodium ion permeability of excitable membranes (PubMed:29726066). 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.[1] [2] [3] In macrophages and melanoma cells, may participate in the control of podosome and invadopodia formation.[4] Publication Abstract from PubMedVoltage-gated sodium channel Na(v)1.6 plays a crucial role in neuronal firing in the central nervous system (CNS). Aberrant function of Na(v)1.6 may lead to epilepsy and other neurological disorders. Specific inhibitors of Na(v)1.6 thus have therapeutic potentials. Here we present the cryo-EM structure of human Na(v)1.6 in the presence of auxiliary subunits beta1 and fibroblast growth factor homologous factor 2B (FHF2B) at an overall resolution of 3.1 A. The overall structure represents an inactivated state with closed pore domain (PD) and all "up" voltage-sensing domains. A conserved carbohydrate-aromatic interaction involving Trp302 and Asn326, together with the beta1 subunit, stabilizes the extracellular loop in repeat I. Apart from regular lipids that are resolved in the EM map, an unprecedented Y-shaped density that belongs to an unidentified molecule binds to the PD, revealing a potential site for developing Na(v)1.6-specific blockers. Structural mapping of disease-related Na(v)1.6 mutations provides insights into their pathogenic mechanism. Cryo-EM structure of human voltage-gated sodium channel Na(v)1.6.,Fan X, Huang J, Jin X, Yan N Proc Natl Acad Sci U S A. 2023 Jan 31;120(5):e2220578120. doi: , 10.1073/pnas.2220578120. Epub 2023 Jan 25. PMID:36696443[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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