6MVX

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

Summary for 6MVX

• Entry DOI: 10.2210/pdb6mvx/pdb
• Related: 6MVV 6MVW
• Descriptor: Ion transport protein, PHOSPHATE ION, Flecainide (3 entities in total)
• Functional Keywords: ion channel voltage-gated sodium channel, membrane protein
• Biological source: Arcobacter butzleri (strain RM4018)
• Total number of polymer chains: 4
• Total formula weight: 133784.43

Authors

Lenaeus, M.J.,Catterall, W.A. (deposition date: 2018-10-28, release date: 2018-12-05, Last modification date: 2024-10-16)

Primary citation

Gamal El-Din, T.M.,Lenaeus, M.J.,Zheng, N.,Catterall, W.A.
Fenestrations control resting-state block of a voltage-gated sodium channel.
Proc. Natl. Acad. Sci. U.S.A., 115:13111-13116, 2018

PubMed Abstract: 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 NaAb, 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 NaAb, 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.

PubMed: 30518562
DOI: 10.1073/pnas.1814928115

Experimental method

X-RAY DIFFRACTION (3.455 Å)