ArticleThe Journal of general physiology2008
hERG gating microdomains defined by S6 mutagenesis and molecular modeling.
Article in The Journal of general physiology, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 61 citations in OpenAlex.
- Forward genetics reveals a conserved CNBHD-CNBHD interface that restrains EAG channel activation to regulate sleep.PLoS genetics · 2026Article
- Molecular Determinants of Voltage-Dependent Gating in Kv11.1 Channels.Advances in experimental medicine and biology · 2026Review
- Article
- The mechanism study ofTranslational cancer research · 2022Article
- Mapping Electromechanical Coupling Pathways in Voltage-Gated Ion Channels: Challenges and the Way Forward.Journal of molecular biology · 2021Review
- Refinement of a cryo-EM structure of hERG: Bridging structure and function.Biophysical journal · 2021Article
- High-throughput discovery of trafficking-deficient variants in the cardiac potassium channel KHeart rhythm · 2020Article
- hERG Function in Light of Structure.Biophysical journal · 2020Review
- The EAG Voltage-Dependent KFrontiers in pharmacology · 2020Review
- Identification of undecylenic acid as EAG channel inhibitor using surface plasmon resonance-based screen of KCNH channels.BMC pharmacology & toxicology · 2019Article
- New Structures and Gating of Voltage-Dependent Potassium (Kv) Channels and Their Relatives: A Multi-Domain and Dynamic Question.International journal of molecular sciences · 2019Review
- Eag1 Voltage-Dependent Potassium Channels: Structure, Electrophysiological Characteristics, and Function in Cancer.The Journal of membrane biology · 2017Review
- Rescue of protein expression defects may not be enough to abolish the pro-arrhythmic phenotype of long QT type 2 mutations.The Journal of physiology · 2016Article
- De novo KCNH1 mutations in four patients with syndromic developmental delay, hypotonia and seizures.Journal of human genetics · 2016Review
- Conservation analysis of residues in the S4-S5 linker and the terminal part of the S5-P-S6 pore modulus in Kv and HCN channels: flexible determinants for the electromechanical coupling.Pflugers Archiv : European journal of physiology · 2015Article
- Voltage-dependent gating of KCNH potassium channels lacking a covalent link between voltage-sensing and pore domains.Nature communications · 2015Article
- The enigmatic cytoplasmic regions of KCNH channels.Journal of molecular biology · 2015Review
- Canine CNGA3 Gene Mutations Provide Novel Insights into Human Achromatopsia-Associated Channelopathies and Treatment.PloS one · 2015Article
- Concerted all-or-none subunit interactions mediate slow deactivation of human ether-à-go-go-related gene K+ channels.The Journal of biological chemistry · 2014Article
- Proline scan of the HERG channel S6 helix reveals the location of the intracellular pore gate.Biophysical journal · 2014Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Human ether-à-go-go-related gene (hERG) channels mediate cardiac repolarization and bind drugs that can cause acquired long QT syndrome and life-threatening arrhythmias. Drugs bind in the vestibule formed by the S6 transmembrane domain, which also contains the activation gate that traps drugs in the vestibule and contributes to their efficacy of block. Although drug-binding residues have been identified, we know little about the roles of specific S6 residues in gating. We introduced cysteine mutations into the hERG channel S6 domain and measured mutational effects on the steady-state distribution and kinetics of transitions between the closed and open states. Energy-minimized molecular models based on the crystal structures of rKv1.2 (open state) and MlotiK1 and KcsA (closed state) provided structural contexts for evaluating mutant residues. The majority of mutations slowed deactivation, shifted conductance voltage curves to more negative potentials, or conferred a constitutive conductance over voltages that normally cause the channel to close. At the most intracellular extreme of the S6 region, Q664, Y667, and S668 were especially sensitive and together formed a ringed domain that occludes the pore in the closed state model. In contrast, mutation of S660, more than a full helical turn away and corresponding by alignment to a critical Shaker gate residue (V478), had little effect on gating. Multiple substitutions of chemically distinct amino acids at the adjacent V659 suggested that, upon closing, the native V659 side chain moves into a hydrophobic pocket but likely does not form the occluding gate itself. Overall, the study indicated that S6 mutagenesis disrupts the energetics primarily of channel closing and identified several residues critical for this process in the native channel.
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