Beschreibung:
<jats:title>Abstract</jats:title><jats:p><jats:italic>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<jats:sub>v</jats:sub>1.2 with artificially shifted S5 sequences modeled into the structure served as a reference case. We docked the known hERG inhibitors (+)‐cisapride, (</jats:italic>S<jats:italic>)‐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,</jats:italic> J. Biol. Chem. <jats:italic><jats:bold>2009</jats:bold>,</jats:italic> 284<jats:italic>, 1000–1008).</jats:italic><jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#bib1">1</jats:ext-link> <jats:italic>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.</jats:italic></jats:p>