Toward a Consensus Model of the hERG Potassium Channel

Anna Stary, Soeren J. Wacker, Lars Boukharta, Ulrich Zachariae, Yasmin Karimi-Nejad, Johan Aqvist, Gert Vriend, Bert L. de Groot

Research output: Contribution to journalArticlepeer-review

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. R Riek, P. C. Chen, A. M. Torres, R S. Bansal, S. Kuyucak, R W. Kuchel, J. I. Vandenberg, J. Biol. Chem. 2009, 284, 1000-1008).([1]) 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.

Original languageEnglish
Pages (from-to)455-467
Number of pages13
JournalChemMedChem
Volume5
Issue number3
DOIs
Publication statusPublished - Mar 2010

Keywords

  • docking
  • hERG
  • model validation
  • molecular dynamics
  • molecular modeling
  • DEPENDENT K+ CHANNEL
  • LONG QT SYNDROME
  • MOLECULAR-DYNAMICS SIMULATIONS
  • PROTEIN SECONDARY STRUCTURE
  • QUALITY ASSESSMENT
  • DRUG-BINDING
  • CARDIAC-ARRHYTHMIA
  • AROMATIC RESIDUES
  • CRYSTAL-STRUCTURE
  • FOLD RECOGNITION

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