Search: onr:"swepub:oai:DiVA.org:uu-136932" >
Toward a Consensus ...
Toward a Consensus Model of the hERG Potassium Channel
-
Stary, Anna (author)
-
Wacker, Soeren J. (author)
-
- Boukharta, Lars (author)
- Uppsala universitet,Institutionen för cell- och molekylärbiologi
-
show more...
-
Zachariae, Ulrich (author)
-
Karimi-Nejad, Yasmin (author)
-
- Åqvist, Johan (author)
- Uppsala universitet,Institutionen för cell- och molekylärbiologi
-
Vriend, Gert (author)
-
de Groot, Bert L. (author)
-
show less...
-
(creator_code:org_t)
- 2010-02-19
- 2010
- English.
-
In: ChemMedChem. - : Wiley. - 1860-7179 .- 1860-7187. ; 5:3, s. 455-467
- Related links:
-
https://pure.mpg.de/...
-
show more...
-
https://urn.kb.se/re...
-
https://doi.org/10.1...
-
show less...
Abstract
Subject headings
Close
- 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.
Subject headings
- NATURVETENSKAP -- Biologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences (hsv//eng)
Keyword
- docking
- hERG
- model validation
- molecular dynamics
- molecular modeling
- Biology
- Biologi
Publication and Content Type
- ref (subject category)
- art (subject category)
Find in a library
To the university's database