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 language | English |
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Pages (from-to) | 455-467 |
Number of pages | 13 |
Journal | ChemMedChem |
Volume | 5 |
Issue number | 3 |
DOIs | |
Publication status | Published - Mar 2010 |
Keywords / Materials (for Non-textual outputs)
- 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