6mvx

NavAb Voltage-gated Sodium Channel, I217C, in Complex with Class 1C Anti-arrhythmic Flecainide

spinqualitylabelsall models 6mvx, resolution 3.46Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6mvx is a 4 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 3.455Å Ligands: K4D, PO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function A8EVM5_ALIB4 Publication Abstract from PubMed Potency of drug action is usually determined by binding to a specific receptor site on target proteins. In contrast to this conventional paradigm, we show here that potency of local anesthetics (LAs) and antiarrhythmic drugs (AADs) that block sodium channels is controlled by fenestrations that allow drug access to the receptor site directly from the membrane phase. Voltage-gated sodium channels initiate action potentials in nerve and cardiac muscle, where their hyperactivity causes pain and cardiac arrhythmia, respectively. LAs and AADs selectively block sodium channels in rapidly firing nerve and muscle cells to relieve these conditions. The structure of the ancestral bacterial sodium channel NaVAb, which is also blocked by LAs and AADs, revealed fenestrations connecting the lipid phase of the membrane to the central cavity of the pore. We cocrystallized lidocaine and flecainide with NavAb, which revealed strong drug-dependent electron density in the central cavity of the pore. Mutation of the contact residue T206 greatly reduced drug potency, confirming this site as the receptor for LAs and AADs. Strikingly, mutations of the fenestration cap residue F203 changed fenestration size and had graded effects on resting-state block by flecainide, lidocaine, and benzocaine, the potencies of which were altered from 51- to 2.6-fold in order of their molecular size. These results show that conserved fenestrations in the pores of sodium channels are crucial pharmacologically and determine the level of resting-state block by widely used drugs. Fine-tuning drug access through fenestrations provides an unexpected avenue for structure-based design of ion-channel-blocking drugs. Fenestrations control resting-state block of a voltage-gated sodium channel.,Gamal El-Din TM, Lenaeus MJ, Zheng N, Catterall WA Proc Natl Acad Sci U S A. 2018 Dec 5. pii: 1814928115. doi:, 10.1073/pnas.1814928115. PMID:30518562 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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