ArticleBiophysical journal2015
Probing binding sites and mechanisms of action of an I(Ks) activator by computations and experiments.
Article in Biophysical journal, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed.
- High-throughput screening identifies a trafficking corrector for long QT syndrome-associated KCNQ1 variants.JCI insight · 2026Article
- Mapping the Functional Landscape ofmedRxiv : the preprint server for health sciences · 2025Article
- Strategies for prolonging ventricular action potential duration without increasing transmural dispersion of repolarization.Physiological reports · 2025Article
- High Throughput Screening Identifies a Small Molecule Trafficking Corrector for Long-QT Syndrome Associated KCNQ1 Variants.bioRxiv : the preprint server for biology · 2025Article
- Voltage sensors.Molecular pharmacology · 2025Review
- The fully activated open state of KCNQ1 controls the cardiac "fight-or-flight" response.PNAS nexus · 2024Article
- A generic binding pocket for small moleculeeLife · 2023Article
- Slowly activating voltage-gated potassium current potentiation by ML277 is a novel cardioprotective intervention.PNAS nexus · 2023Article
- IBiomedicines · 2023Article
- Structural mechanisms for the activation of human cardiac KCNQ1 channel by electro-mechanical coupling enhancers.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Structural and electrophysiological basis for the modulation of KCNQ1 channel currents by ML277.Nature communications · 2022Article
- Positive rate-dependent action potential prolongation by modulating potassium ion channels.Physiological reports · 2022Article
- Two small-molecule activators share similar effector sites in the KCNQ1 channel pore but have distinct effects on voltage sensor movements.Frontiers in physiology · 2022Article
- ML277 regulates KCNQ1 single-channel amplitudes and kinetics, modified by voltage sensor state.The Journal of general physiology · 2021Article
- Chemical modulation of Kv7 potassium channels.RSC medicinal chemistry · 2021Review
- Insights into Cardiac IKs (KCNQ1/KCNE1) Channels Regulation.International journal of molecular sciences · 2020Review
- The small molecule GAT1508 activates brain-specific GIRK1/2 channel heteromers and facilitates conditioned fear extinction in rodents.The Journal of biological chemistry · 2020Article
- Gating and Regulation of KCNQ1 and KCNQ1 + KCNE1 Channel Complexes.Frontiers in physiology · 2020Review
- Structures Illuminate Cardiac Ion Channel Functions in Health and in Long QT Syndrome.Frontiers in pharmacology · 2020Review
- ML277 specifically enhances the fully activated open state of KCNQ1 by modulating VSD-pore coupling.eLife · 2019Article
Corrections and comments
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Authors and funding
7 authors.
Funding
Abstract
The slow delayed rectifier (IKs) channel is composed of the KCNQ1 channel and KCNE1 auxiliary subunit, and functions to repolarize action potentials in the human heart. IKs activators may provide therapeutic efficacy for treating long QT syndromes. Here, we show that a new KCNQ1 activator, ML277, can enhance IKs amplitude in adult guinea pig and canine ventricular myocytes. We probe its binding site and mechanism of action by computational analysis based on our recently reported KCNQ1 and KCNQ1/KCNE1 3D models, followed by experimental validation. Results from a pocket analysis and docking exercise suggest that ML277 binds to a side pocket in KCNQ1 and the KCNE1-free side pocket of KCNQ1/KCNE1. Molecular-dynamics (MD) simulations based on the most favorable channel/ML277 docking configurations reveal a well-defined ML277 binding space surrounded by the S2-S3 loop and S4-S5 helix on the intracellular side, and by S4-S6 transmembrane helices on the lateral sides. A detailed analysis of MD trajectories suggests two mechanisms of ML277 action. First, ML277 restricts the conformational dynamics of the KCNQ1 pore, optimizing K(+) ion coordination in the selectivity filter and increasing current amplitudes. Second, ML277 binding induces global motions in the channel, including regions critical for KCNQ1 gating transitions. We conclude that ML277 activates IKs by binding to an intersubunit space and allosterically influencing pore conductance and gating transitions. KCNE1 association protects KCNQ1 from an arrhythmogenic (constitutive current-inducing) effect of ML277, but does not preclude its current-enhancing effect.
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