title: 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.
authors.affiliation: Computational Biomolecular Dynamics Group, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany. anna.stary@univie.ac.at
authors.forename: Anna
authors.initials: A
authors.lastname: Stary
authors.forename: Sören J
authors.initials: SJ
authors.lastname: Wacker
authors.forename: Lars
authors.initials: L
authors.lastname: Boukharta
authors.forename: Ulrich
authors.initials: U
authors.lastname: Zachariae
authors.forename: Yasmin
authors.initials: Y
authors.lastname: Karimi-Nejad
authors.forename: Johan
authors.initials: J
authors.lastname: Aqvist
authors.forename: Gert
authors.initials: G
authors.lastname: Vriend
authors.forename: Bert L
authors.initials: BL
authors.lastname: de Groot
mesh_terms: D000595:Amino Acid Sequence; D001578:Benzopyrans / Q000737:chemistry / Q000494:pharmacology; D020117:Cisapride / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D016593:Terfenadine / Q000737:chemistry / Q000494:pharmacology
chemical_list: D001578:Benzopyrans; D051638:Ether-A-Go-Go Potassium Channels; D010880:Piperidines; C087257:L 706000; D016593:Terfenadine; D020117:Cisapride