Toward a Consensus Model of the hERG Potassium Channel

Abstract

Malfunction of hERG potassium channels, due to inherited mutations or inhibition by drugs, can cause long QT syndrome, which can lead to life-threatening arrhythmias. A three-dimensional structure of hERG is a prerequisite to understand the molecular basis of hERG malfunction. To achieve a consensus model, we carried out an extensive analysis of hERG models based on various alignments of helix S5. We analyzed seven models using a combination of conventional geometry/packing/normality validation methods as well as molecular dynamics simulations and molecular docking. A synthetic test set with the X-ray crystal structure of K(v)1.2 with artificially shifted S5 sequences modeled into the structure served as a reference case. We docked the known hERG inhibitors (+)-cisapride, (S)-terfenadine, and MK-499 into the hERG models and simulation snapshots. None of the single analyses unambiguously identified a preferred model, but the combination of all three revealed that there is only one model that fulfils all quality criteria. This model is confirmed by a recent mutation scanning experiment (P. Ju, G. Pages, R. P. Riek, P. C. Chen, A. M. Torres, P. S. Bansal, S. Kuyucak, P. W. Kuchel, J. I. Vandenberg, J. Biol. Chem. 2009, 284, 1000-1008). We expect the modeled structure to be useful as a basis both for computational studies of channel function and kinetics as well as the design of experiments.

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

“…Two recent studies have postulated direct interactions between Thr-618 of the pore helix and either His-562 (44) or Trp-568 (35) on the S5 helix. The discrepancy between these two studies highlights the uncertainty in aligning the S5 helix of Kv11.1 channels with that of other Kv channel proteins due, in part, to a low degree of homology within this region (45,46). Mutation of His-562 (44,45,47), or 45,47) produced mostly nonexpressing/nonfunctional channels, or in a few cases, abolished the inactivation process entirely (35).…”

Mechanism of hERG Channel Block by the Psychoactive Indole Alkaloid Ibogaine

“…The recently published hERG homology model ("model 6") (Stary et al, 2010) after 50-ns molecular dynamics simulations was used as a starting point for docking investigations. Coordinates of ibogaine were obtained from the Pubchem structure database (http://pubchem.ncbi.nlm.nih.gov/), and the geometry was optimized with Hartree-Fock, 6-31G* basis set, implemented in Gaussian09 (Frisch et al, 2009).…”

“…To further support the notion that ibogaine binds the channel's inner cavity, we applied molecular drug docking to investigate the structural interactions of ibogaine with a previously published hERG homology model (Stary et al, 2010). These simulations suggest that ibogaine binds to the central cavity of hERG and forms hydrophobic interactions with the aromatic rings of Phe656 …”

Molecular Determinants for Activation of HumanEther-à-go-go-relatedGene 1 Potassium Channels by 3-Nitro-N-(4-phenoxyphenyl) Benzamide

“…The homology model of the closed-channel conformation was generated with Modeller 9v7 using the KcsA crystal structure (Protein Data Bank ID 2HVK) as a template. Modeling details, including coordinates for the open conformation, have been described previously (Stary et al, 2010).…”