Toward a Consensus Model of the hERG Potassium Channel
2010 (English)In: ChemMedChem, ISSN 1860-7179, Vol. 5, no 3, 455-467 p.Article in journal (Refereed) Published
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).() 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.
Place, publisher, year, edition, pages
2010. Vol. 5, no 3, 455-467 p.
docking, hERG, model validation, molecular dynamics, molecular modeling
IdentifiersURN: urn:nbn:se:uu:diva-136932DOI: 10.1002/cmdc.200900461ISI: 000275521200015PubMedID: 20104563OAI: oai:DiVA.org:uu-136932DiVA: diva2:377710