8dj0

Crystal structure of NavAb L123T as a basis for the human Nav1.7 Inherited Erythromelalgia I848T mutation

spinqualitylabelsall models 8dj0, resolution 2.70Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8dj0 is a 1 chain structure with sequence from Aliarcobacter butzleri RM4018. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.7Å Ligands: CPS, PX4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function A8EVM5_ALIB4 Publication Abstract from PubMed Gain-of-function mutations in voltage-gated sodium channel Na(V)1.7 cause severe inherited pain syndromes, including inherited erythromelalgia (IEM). The structural basis of these disease mutations, however, remains elusive. Here, we focused on three mutations that all substitute threonine residues in the alpha-helical S4-S5 intracellular linker that connects the voltage sensor to the pore: Na(V)1.7/I234T, Na(V)1.7/I848T, and Na(V)1.7/S241T in order of their positions in the amino acid sequence within the S4-S5 linkers. Introduction of these IEM mutations into the ancestral bacterial sodium channel Na(V)Ab recapitulated the pathogenic gain-of-function of these mutants by inducing a negative shift in the voltage dependence of activation and slowing the kinetics of inactivation. Remarkably, our structural analysis reveals a common mechanism of action among the three mutations, in which the mutant threonine residues create new hydrogen bonds between the S4-S5 linker and the pore-lining S5 or S6 segment in the pore module. Because the S4-S5 linkers couple voltage sensor movements to pore opening, these newly formed hydrogen bonds would stabilize the activated state substantially and thereby promote the 8 to 18 mV negative shift in the voltage dependence of activation that is characteristic of the Na(V)1.7 IEM mutants. Our results provide key structural insights into how IEM mutations in the S4-S5 linkers may cause hyperexcitability of Na(V)1.7 and lead to severe pain in this debilitating disease. Structural basis for severe pain caused by mutations in the S4-S5 linkers of voltage-gated sodium channel Na(V)1.7.,Wisedchaisri G, Gamal El-Din TM, Zheng N, Catterall WA Proc Natl Acad Sci U S A. 2023 Apr 4;120(14):e2219624120. doi: , 10.1073/pnas.2219624120. Epub 2023 Mar 30. PMID:36996107 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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