7tci
Structure of Xenopus KCNQ1-CaM in complex with ML277
Structural highlights
FunctionKCNQ1_XENLA Potassium channel that plays an important role in a number of tissues, including heart, inner ear, stomach and colon (By similarity). Associates with KCNE beta subunits that modulates current kinetics (By similarity). Induces a voltage-dependent by rapidly activating and slowly deactivating potassium-selective outward current (By similarity). Promotes also a delayed voltage activated potassium current showing outward rectification characteristic (By similarity). During beta-adrenergic receptor stimulation participates in cardiac repolarization by associating with KCNE1 to form the I(Ks) cardiac potassium current that increases the amplitude and slows down the activation kinetics of outward potassium current I(Ks) (By similarity). When associated with KCNE3, forms the potassium channel that is important for cyclic AMP-stimulated intestinal secretion of chloride ions (By similarity). When associated with KCNE2, forms a heterooligomer complex leading to currents with an apparently instantaneous activation, a rapid deactivation process and a linear current-voltage relationship and decreases the amplitude of the outward current (By similarity). When associated with KCNE4, inhibits voltage-gated potassium channel activity (By similarity). When associated with KCNE5, this complex only conducts current upon strong and continued depolarization (By similarity).[UniProtKB:P51787][UniProtKB:P97414][UniProtKB:Q9Z0N7] Publication Abstract from PubMedThe KCNQ1 ion channel plays critical physiological roles in electrical excitability and K(+) recycling in organs including the heart, brain, and gut. Loss of function is relatively common and can cause sudden arrhythmic death, sudden infant death, epilepsy and deafness. Here, we report cryogenic electron microscopic (cryo-EM) structures of Xenopus KCNQ1 bound to Ca(2+)/Calmodulin, with and without the KCNQ1 channel activator, ML277. A single binding site for ML277 was identified, localized to a pocket lined by the S4-S5 linker, S5 and S6 helices of two separate subunits. Several pocket residues are not conserved in other KCNQ isoforms, explaining specificity. MD simulations and point mutations support this binding location for ML277 in open and closed channels and reveal that prevention of inactivation is an important component of the activator effect. Our work provides direction for therapeutic intervention targeting KCNQ1 loss of function pathologies including long QT interval syndrome and seizures. Structural and electrophysiological basis for the modulation of KCNQ1 channel currents by ML277.,Willegems K, Eldstrom J, Kyriakis E, Ataei F, Sahakyan H, Dou Y, Russo S, Van Petegem F, Fedida D Nat Commun. 2022 Jun 29;13(1):3760. doi: 10.1038/s41467-022-31526-7. PMID:35768468[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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