Molecular Determinants of hERG Channel Block

@article{Kamiya2006MolecularDO,
  title={Molecular Determinants of hERG Channel Block},
  author={Kaichiro Kamiya and Ryoko Niwa and John S. Mitcheson and Michael C Sanguinetti},
  journal={Molecular Pharmacology},
  year={2006},
  volume={69},
  pages={1709 - 1716}
}
Drug-induced block of cardiac hERG K+ channels causes acquired long QT syndrome. Here, we characterized the molecular mechanism of hERG block by two low-potency drugs (Nifekalant and bepridil) and two high-potency drugs 1-[2-(6-methyl-2pyridyl)ethyl]-4-(4-methylsulfonyl aminobenzoyl)piperidine (E-4031) and dofetilide). Channels were expressed in Xenopus laevis oocytes, and currents were measured using the two-microelectrode voltage-clamp technique. All four drugs progressively reduced hERG… Expand
Structural implications of hERG K+ channel block by a high-affinity minimally structured blocker
TLDR
HERG channel inhibition by a minimally structured high-affinity hERG inhibitor, Cavalli-2, composed of three phenyl groups linked by polymethylene spacers around a central amino group, chosen to probe the spatial arrangement of side chain groups in the high-Affinity drug-binding site of the hERG pore is characterized. Expand
State-dependent dissociation of HERG channel inhibitors
TLDR
The data suggest that apparently 'trapped' drugs (group 2) dissociate from the open channel state whereas group 1 compounds dissociated from open and resting states ('use-dependent' dissociation). Expand
Molecular determinants of hERG channel block by terfenadine and cisapride.
TLDR
The findings suggest that different drugs can adopt distinct modes of binding to the central cavity of hERG, and confirm previous findings that polar residues located near the base of the pore helix and aromatic residues located in the S6 domain are key molecular determinants of the hERG drug binding site. Expand
The molecular determinants of R-roscovitine block of hERG channels
TLDR
Two-electrode voltage clamp recordings from Xenopus oocytes expressing wild-type or mutant hERG channels demonstrated that while T623, Y652, and F656 are critical for R-roscovitine-mediated inhibition, S624 may not be, and these findings lend support for the recent Comprehensive In Vitro Proarrhythmia Assay (CiPA) guidelines. Expand
Molecular determinants of hERG potassium channel inhibition by disopyramide.
TLDR
Computational docking with the hERG model showed that DISO did not exhibit a single unique binding pose; instead several low energy binding poses at the lower end of the pore cavity favoured interactions with Y652 and F656, consistent with the minimal effect of mutation of these residues on drug block. Expand
The molecular determinants of R-roscovitine block of hERG channels
TLDR
Two-electrode voltage clamp recordings from Xenopus oocytes expressing wild-type or hERG pore mutant channels demonstrated that while T623, Y652, and F656 are critical for R-roscovitine-mediated inhibition, S624 may not be, and this could guide future drug screens. Expand
Probing the molecular basis of hERG drug block with unnatural amino acids
TLDR
Assessment of terfenadine, quinidine, and dofetilide block did not reveal evidence of a cation-π interaction at either aromatic residue, but shows that certain fluoro-Phe substitutions at position 652 result in weaker  drug potency. Expand
Structural modeling of the hERG potassium channel and associated drug interactions
TLDR
Computational models of hERG potassium channel provide structural insights into an inactivated state and associated drug interactions and will be useful to study ion channel modulation by small molecules. Expand
Investigating the state dependence of drug binding in hERG channels using a trapped-open channel phenotype
TLDR
The role of inactivation is directly assessed in cisparide and terfenadine drug binding in mutant (I663P) hERG channels where the activation gate is trapped-open and shows that inactivation, ion selectivity and high affinity drug binding are preserved in I663P mutant channels. Expand
The Link between Inactivation and High-Affinity Block of hERG1 Channels
TLDR
Findings indicate that S620T or S631A substitutions can allosterically disrupt drug binding by a mechanism that is independent of their effects on inactivation gating. Expand
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References

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Structural Determinants of HERG Channel Block by Clofilium and Ibutilide
TLDR
The pore helix residues are important components of the HERG drug binding site, and may be particularly important for drugs with polar substituents, such as a halogen or a methanesulfonamide (e.g., ibutilide). Expand
High affinity HERG K(+) channel blockade by the antiarrhythmic agent dronedarone: resistance to mutations of the S6 residues Y652 and F656.
TLDR
It is demonstrated that high affinity drug blockade of I(HERG) can occur without a strong dependence on the Y652 and F656 aromatic amino-acid residues. Expand
Class III antiarrhythmic drugs block HERG, a human cardiac delayed rectifier K+ channel. Open-channel block by methanesulfonanilides.
TLDR
Data indicate that MK-499 preferentially blocks open HERG channels and further support the conclusion that HERG subunits form I(Kr) channels in cardiac myocytes. Expand
The Low-Potency, Voltage-Dependent HERG Blocker Propafenone—Molecular Determinants and Drug Trapping
TLDR
Homology models of HERG based on KcsA and MthK crystal structures, representing the closed and open forms of the channel, suggest propafenone is trapped in the inner cavity and is unable to interact exclusively with Phe656 in the closed state (whereas exclusive interactions between propafanone and P he656 are found in the open-channel model). Expand
Molecular Determinants of Voltage-dependent Human Ether-a-Go-Go Related Gene (HERG) K+ Channel Block*
TLDR
The experimental findings and modeling suggest that chloroquine preferentially blocks open HERG channels by cation-π and π-stacking interactions with Tyr-652 and Phe-656 of multiple subunits. Expand
Blockade of HERG potassium currents by fluvoxamine: incomplete attenuation by S6 mutations at F656 or Y652
TLDR
Characteristics of block were consistent with a component of closed channel blockade and dependence on open and inactivated channel states, and fluvoxamine is therefore quite distinct in this regard from previously studied agents. Expand
Lidoflazine is a high affinity blocker of the HERG K(+)channel.
TLDR
It is concluded that lidoflazine produces high affinity blockade of the alpha subunit of the HERG channel by binding to aromatic amino acid residues within the channel pore and this is likely to represent the molecular mechanism of QT interval prolongation by this drug. Expand
Physicochemical Features of the hERG Channel Drug Binding Site*
TLDR
Together, these findings assign specific residues to receptor fields predicted by pharmacophore models of hERG channel blockers and provide a refined molecular understanding of the drug binding site. Expand
Voltage-dependent profile of human ether-a-go-go-related gene channel block is influenced by a single residue in the S6 transmembrane domain.
TLDR
The results suggest that voltage-dependent block of HERG results from gating-dependent changes in the orientation of Y652, a critical component of the drug binding site, and not from a transmembrane field effect on a charged drug molecule. Expand
Toward a pharmacophore for drugs inducing the long QT syndrome: insights from a CoMFA study of HERG K(+) channel blockers.
TLDR
A pharmacophore for QT-prolonging drugs, along with a 3D QSAR (CoMFA) study for a series of very structurally variegate HERG K(+) channel blockers, and a theoretical screening tool able to predict whether a new molecule can interact with the HERG channel and eventually induce the long QT syndrome. Expand
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