Drug block of the hERG potassium channel: Insight from modeling

Abstract

Many commonly used, structurally diverse, drugs block the human ether-a-go-go-related gene (hERG) K(+) channel to cause acquired long QT syndrome, which can lead to sudden death via lethal cardiac arrhythmias. This undesirable side effect is a major hurdle in the development of safe drugs. To gain insight about the structure of hERG and the nature of drug block we have produced structural models of the channel pore domain, into each of which we have docked a set of 20 hERG blockers. In the absence of an experimentally determined three-dimensional structure of hERG, each of the models was validated against site-directed mutagenesis data. First, hERG models were produced of the open and closed channel states, based on homology with the prokaryotic K(+) channel crystal structures. The modeled complexes were in partial agreement with the mutagenesis data. To improve agreement with mutagenesis data, a KcsA-based model was refined by rotating the four copies of the S6 transmembrane helix half a residue position toward the C-terminus, so as to place all residues known to be involved in drug binding in positions lining the central cavity. This model produces complexes that are consistent with mutagenesis data for smaller, but not larger, ligands. Larger ligands could be accommodated following refinement of this model by enlarging the cavity using the inherent flexibility about the glycine hinge (Gly648) in S6, to produce results consistent with the experimental data for the majority of ligands tested.

Pore Helices Play a Dynamic Role as Integrators of Domain Motion during Kv11.1 Channel Inactivation Gating

“…It has previously been suggested that the inner (cytoplasmic) half of the S6 helices of Kv11.1 channels (Gly-648 to Tyr-667) undergoes a rotation at some point during the transition between open and inactivated states and that this rotation enhances sensitivity to block by some drugs (48,49). Whether a similar rotation or a distinct conformational change occurs in the upper (extracellular) half of the S6 helix (Phe-640 to Ile-647) remains to be determined.…”

Computer Simulations of Structure–Activity Relationships for hERG Channel Blockers

“…5,14 The short pore helix, the selectivity filter, and the innermost S6 helices lining the pore can, however, be confidently aligned on the basis of conservation of the filter region and a glycine hinge in S6. 15,16 The situation is more ambiguous for the S5 helices that pack against the S6 helices in the tetrameric structure, and several alignments of S5 against K + channels of known structure have been published. 15À18 We have recently reported an analysis of seven different alignments and 3D pore models utilizing conventional 3D structure quality validation methods as well as molecular dynamics (MD) simulations.…”

Stereoselective Block of hERG Channel by Bupivacaine Scrutinized at Molecular Level

“…The binding site was defined following the definition of Stansfeld et al, [19] namely as all protein atoms within 20 Å from the natural K + ion S cav . This ion is not present in the structure, but coordinates were retrieved from backbone overlay of the selectivity filter of KcsA crystallized subunit including K + ions (pdb entry: 1k4c) and our target structure.…”