7k18
From Proteopedia
Cardiac Sodium channel with toxin bound
Structural highlights
FunctionSCN5A_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]GFP_AEQVI Energy-transfer acceptor. Its role is to transduce the blue chemiluminescence of the protein aequorin into green fluorescent light by energy transfer. Fluoresces in vivo upon receiving energy from the Ca(2+)-activated photoprotein aequorin. Publication Abstract from PubMedVoltage-gated sodium (Na(V)) channels initiate action potentials in excitable cells, and their function is altered by potent gating-modifier toxins. The alpha-toxin LqhIII from the deathstalker scorpion inhibits fast inactivation of cardiac Na(V)1.5 channels with IC(50) = 11.4 nM. Here we reveal the structure of LqhIII bound to Na(V)1.5 at 3.3 A resolution by cryo-EM. LqhIII anchors on top of voltage-sensing domain IV, wedged between the S1-S2 and S3-S4 linkers, which traps the gating charges of the S4 segment in a unique intermediate-activated state stabilized by four ion-pairs. This conformational change is propagated inward to weaken binding of the fast inactivation gate and favor opening the activation gate. However, these changes do not permit Na(+) permeation, revealing why LqhIII slows inactivation of Na(V) channels but does not open them. Our results provide important insights into the structural basis for gating-modifier toxin binding, voltage-sensor trapping, and fast inactivation of Na(V) channels. Structural basis for voltage-sensor trapping of the cardiac sodium channel by a deathstalker scorpion toxin.,Jiang D, Tonggu L, Gamal El-Din TM, Banh R, Pomes R, Zheng N, Catterall WA Nat Commun. 2021 Jan 4;12(1):128. doi: 10.1038/s41467-020-20078-3. PMID:33397917[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. Loading citation details.. Citations No citations found See AlsoReferences
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