4mz3

Crystal structure of the voltage-gated sodium channel beta 4 subunit extracellular domain, C131W mutant

spinqualitylabelsall models 4mz3, resolution 1.74Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4mz3 is a 2 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: X-ray diffraction, Resolution 1.741Å Ligands: CME Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease SCN4B_HUMAN Romano-Ward syndrome. The disease is caused by mutations affecting the gene represented in this entry. Function SCN4B_HUMAN Modulates channel gating kinetics. Causes negative shifts in the voltage dependence of activation of certain alpha sodium channels, but does not affect the voltage dependence of inactivation (By similarity). Publication Abstract from PubMed Voltage-gated sodium (Nav) channels are embedded in a multicomponent membrane signaling complex that plays a crucial role in cellular excitability. Although the mechanism remains unclear, beta-subunits modify Nav channel function and cause debilitating disorders when mutated. While investigating whether beta-subunits also influence ligand interactions, we found that beta4 dramatically alters toxin binding to Nav1.2. To explore these observations further, we solved the crystal structure of the extracellular beta4 domain and identified (58)Cys as an exposed residue that, when mutated, eliminates the influence of beta4 on toxin pharmacology. Moreover, our results suggest the presence of a docking site that is maintained by a cysteine bridge buried within the hydrophobic core of beta4. Disrupting this bridge by introducing a beta1 mutation implicated in epilepsy repositions the (58)Cys-containing loop and disrupts beta4 modulation of Nav1.2. Overall, the principles emerging from this work (i) help explain tissue-dependent variations in Nav channel pharmacology; (ii) enable the mechanistic interpretation of beta-subunit-related disorders; and (iii) provide insights in designing molecules capable of correcting aberrant beta-subunit behavior. Crystallographic insights into sodium-channel modulation by the beta4 subunit.,Gilchrist J, Das S, Van Petegem F, Bosmans F Proc Natl Acad Sci U S A. 2013 Dec 17;110(51):E5016-24. doi:, 10.1073/pnas.1314557110. Epub 2013 Dec 2. PMID:24297919 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Ion channels 3D structures

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