Structural Determinants of HERG Channel Block by Clofilium and Ibutilide

  title={Structural Determinants of HERG Channel Block by Clofilium and Ibutilide},
  author={Matthew D Perry and Marcel J. de Groot and Ray M Helliwell and Derek J. Leishman and Martin Tristani-Firouzi and Michael C Sanguinetti and John S. Mitcheson},
  journal={Molecular Pharmacology},
  pages={240 - 249}
Block of human ether-a-go-go related gene (HERG) K+ channels by a variety of medications has been linked to acquired long QT syndrome, a disorder of cardiac repolarization that predisposes to lethal arrhythmias. The drug-binding site is composed of residues that face into the central cavity of the channel. Two aromatic residues located on the S6 domain (Tyr652 and Phe656) are particularly important structural determinants of drug block. The role of pore helix residues (Thr623, Ser624, Val625… 

Figures and Tables from this paper

Drug Binding Interactions in the Inner Cavity of hERG Channels: Molecular Insights from Structure-Activity Relationships of Clofilium and Ibutilide Analogs
Block of human ether-a-go-go related gene (hERG) K+ channels by otherwise useful drugs is the most common cause of long QT syndrome, a disorder of cardiac repolarization that predisposes patients to
Structural implications of hERG K+ channel block by a high-affinity minimally structured blocker
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.
The Low-Potency, Voltage-Dependent HERG Blocker Propafenone—Molecular Determinants and Drug Trapping
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).
Molecular determinants of hERG channel block by terfenadine and cisapride.
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.
Molecular Determinants of hERG Channel Block
The molecular determinants of hERG channel block were defined by using a site-directed mutagenesis approach and it is concluded that the binding site is not identical for all drugs that preferentially block hERG in the open state.
Probing the molecular basis of hERG drug block with unnatural amino acids
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.
The molecular determinants of R-roscovitine block of hERG channels
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.
Mutational Analysis of Block and Facilitation of HERG Current by A Class III Anti-Arrhythmic Agent, Nifekalant
Chemicals and toxins are useful tools to elucidate the structure-function relationship of various proteins including ion channels. The HERG channel is blocked by many compounds and this may cause
Revealing Molecular Determinants of hERG Blocker and Activator Binding
A hERG conformational state allowing discrimination of blockers vs non-blockers from docking is identified and the binding pocket agrees with mutagenesis data and blocker binding modes fit the hERG blocker pharmacophore.
An Allosteric Mechanism for Drug Block of the Human Cardiac Potassium Channel KCNQ1
The data support a model in which open state block of this channel occurs not via binding to a site directly in the pore but rather by a novel allosteric mechanism: drug access to a side pocket generated in the open-state channel configuration and lined by S6 and S4-S5 residues.


Molecular Determinants of Voltage-dependent Human Ether-a-Go-Go Related Gene (HERG) K+ Channel Block*
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.
Molecular determinants of high-affinity drug binding to HERG channels.
New studies are shedding light on the structural basis of drug binding and the gating-dependent repositioning of key residues in the inner cavity of HERG, which are responsible for the unusual sensitivity of HerG to pharmacological agents.
Inhibition of hEAG1 and hERG1 potassium channels by clofilium and its tertiary analogue LY97241
We investigated the inhibition of hEAG1 potassium channels, expressed in mammalian cells and Xenopus oocytes, by several blockers that have previously been reported to be blockers of hERG1 channels.
Blockade of HERG potassium currents by fluvoxamine: incomplete attenuation by S6 mutations at F656 or Y652
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.
Trapping of a Methanesulfonanilide by Closure of the Herg Potassium Channel Activation Gate
The findings provide direct evidence that the mechanism of slow recovery from HERG channel block by methanesulfonanilides is due to trapping of the compound in the inner vestibule by closure of the activation gate, and suggests that the Vestibule of this channel is larger than the well studied Shaker K+ channel.
Voltage-dependent profile of human ether-a-go-go-related gene channel block is influenced by a single residue in the S6 transmembrane domain.
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.
Open channel block of HERG K(+) channels by vesnarinone.
It is concluded that vesnarinone preferentially blocks open HERG channels, with little effect on channels in the rested or inactivated state, and may contribute to the favorable frequency-dependent prolongation in APD.
HERG K+ channels: friend and foe.
Toward a pharmacophore for drugs inducing the long QT syndrome: insights from a CoMFA study of HERG K(+) channel blockers.
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.
I(Kr): the hERG channel.
  • G. Tseng
  • Biology, Medicine
    Journal of molecular and cellular cardiology
  • 2001
G.-N. Tseng. I(Kr): The hERG Channel. Journal of Molecular and Cellular Cardiology (2001) 33, 835-849. The rapid delayed rectifier (I(Kr)) channel is important for cardiac action potential