7fbs | pdb_00007fbs
structure of a channel
Structural highlights
Function[SCN5A_RAT] This protein mediates the voltage-dependent sodium ion permeability of excitable membranes. 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. It is a tetrodotoxin-resistant Na(+) channel isoform. This channel is responsible for the initial upstroke of the action potential. Channel inactivation is regulated by intracellular calcium levels.[UniProtKB:Q14524][UniProtKB:Q9JJV9] Publication Abstract from PubMedThe heartbeat is initiated by voltage-gated sodium channel NaV1.5, which opens rapidly and triggers the cardiac action potential; however, the structural basis for pore opening remains unknown. Here, we blocked fast inactivation with a mutation and captured the elusive open-state structure. The fast inactivation gate moves away from its receptor, allowing asymmetric opening of pore-lining S6 segments, which bend and rotate at their intracellular ends to dilate the activation gate to approximately 10 A diameter. Molecular dynamics analyses predict physiological rates of Na(+) conductance. The open-state pore blocker propafenone binds in a high-affinity pose, and drug-access pathways are revealed through the open activation gate and fenestrations. Comparison with mutagenesis results provides a structural map of arrhythmia mutations that target the activation and fast inactivation gates. These results give atomic-level insights into molecular events that underlie generation of the action potential, open-state drug block, and fast inactivation of cardiac sodium channels, which initiate the heartbeat. Open-state structure and pore gating mechanism of the cardiac sodium channel.,Jiang D, Banh R, Gamal El-Din TM, Tonggu L, Lenaeus MJ, Pomes R, Zheng N, Catterall WA Cell. 2021 Sep 4. pii: S0092-8674(21)00995-8. doi: 10.1016/j.cell.2021.08.021. PMID:34520724[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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