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Toward a Consensus ...
Toward a Consensus Model of the hERG Potassium Channel
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Stary, Anna (författare)
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Wacker, Soeren J. (författare)
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- Boukharta, Lars (författare)
- Uppsala universitet,Institutionen för cell- och molekylärbiologi
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Zachariae, Ulrich (författare)
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Karimi-Nejad, Yasmin (författare)
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- Åqvist, Johan (författare)
- Uppsala universitet,Institutionen för cell- och molekylärbiologi
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Vriend, Gert (författare)
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de Groot, Bert L. (författare)
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(creator_code:org_t)
- 2010-02-19
- 2010
- Engelska.
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Ingår i: ChemMedChem. - : Wiley. - 1860-7179 .- 1860-7187. ; 5:3, s. 455-467
- Relaterad länk:
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https://pure.mpg.de/...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- NATURVETENSKAP -- Biologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences (hsv//eng)
Nyckelord
- docking
- hERG
- model validation
- molecular dynamics
- molecular modeling
- Biology
- Biologi
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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