ArticleProteins2010
Structural refinement of the hERG1 pore and voltage-sensing domains with ROSETTA-membrane and molecular dynamics simulations.
Article in Proteins, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 51 citations in OpenAlex.
- Atomistic mechanisms of the regulation of small-conductance CaProceedings of the National Academy of Sciences of the United States of America · 2024Article
- Structural modeling of NaBiophysics reports · 2021Article
- Refinement of a cryo-EM structure of hERG: Bridging structure and function.Biophysical journal · 2021Article
- Investigation of PDE5/PDE6 and PDE5/PDE11 selective potent tadalafil-like PDE5 inhibitors using combination of molecular modeling approaches, molecular fingerprint-based virtual screening protocols and structure-based pharmacophore development.Journal of enzyme inhibition and medicinal chemistry · 2017Article
- Comparative study of the structure and interaction of the pore helices of the hERG and Kv1.5 potassium channels in model membranes.European biophysics journal : EBJ · 2017Article
- Potassium channels in the heart: structure, function and regulation.The Journal of physiology · 2017Review
- Role of the pH in state-dependent blockade of hERG currents.Scientific reports · 2016Article
- Improving homology modeling of G-protein coupled receptors through multiple-template derived conserved inter-residue interactions.Journal of computer-aided molecular design · 2015Article
- NS1643 interacts around L529 of hERG to alter voltage sensor movement on the path to activation.Biophysical journal · 2015Article
- Computational modeling of membrane proteins.Proteins · 2015Review
- Rehabilitating drug-induced long-QT promoters: in-silico design of hERG-neutral cisapride analogues with retained pharmacological activity.BMC pharmacology & toxicology · 2014Article
- Hydrophobic plug functions as a gate in voltage-gated proton channels.Proceedings of the National Academy of Sciences of the United States of America · 2014Article
- Structure driven design of novel human ether-a-go-go-related-gene channel (hERG1) activators.PloS one · 2014Article
- Functional interactions of voltage sensor charges with an S2 hydrophobic plug in hERG channels.The Journal of general physiology · 2013Article
- Two conserved arginine residues from the SK3 potassium channel outer vestibule control selectivity of recognition by scorpion toxins.The Journal of biological chemistry · 2013Article
- Components of gating charge movement and S4 voltage-sensor exposure during activation of hERG channels.The Journal of general physiology · 2013Article
- Insights into hERG K+ channel structure and function from NMR studies.European biophysics journal : EBJ · 2013Review
- Voltage-dependent gating of HERG potassium channels.Frontiers in pharmacology · 2012Article
- Article
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
Abstract
The hERG1 gene (Kv11.1) encodes a voltage-gated potassium channel. Mutations in this gene lead to one form of the Long QT Syndrome (LQTS) in humans. Promiscuous binding of drugs to hERG1 is known to alter the structure/function of the channel leading to an acquired form of the LQTS. Expectably, creation and validation of reliable 3D model of the channel have been a key target in molecular cardiology and pharmacology for the last decade. Although many models were built, they all were limited to pore domain. In this work, a full model of the hERG1 channel is developed which includes all transmembrane segments. We tested a template-driven de-novo design with ROSETTA-membrane modeling using side-chain placements optimized by subsequent molecular dynamics (MD) simulations. Although backbone templates for the homology modeled parts of the pore and voltage sensors were based on the available structures of KvAP, Kv1.2 and Kv1.2-Kv2.1 chimera channels, the missing parts are modeled de-novo. The impact of several alignments on the structure of the S4 helix in the voltage-sensing domain was also tested. Herein, final models are evaluated for consistency to the reported structural elements discovered mainly on the basis of mutagenesis and electrophysiology. These structural elements include salt bridges and close contacts in the voltage-sensor domain; and the topology of the extracellular S5-pore linker compared with that established by toxin foot-printing and nuclear magnetic resonance studies. Implications of the refined hERG1 model to binding of blockers and channels activators (potent new ligands for channel activations) are discussed.
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Registered trials
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