A comprehensive structural model for the human KCNQ1/KCNE1 ion channel.

Autor: Jalily Hasani H; Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada., Ahmed M; Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada., Barakat K; Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada; Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada; Li Ka Shing Applied Virology Institute, University of Alberta, Edmonton, Alberta, Canada. Electronic address: kbarakat@ualberta.ca.
Jazyk: angličtina
Zdroj: Journal of molecular graphics & modelling [J Mol Graph Model] 2017 Nov; Vol. 78, pp. 26-47. Date of Electronic Publication: 2017 Sep 29.
DOI: 10.1016/j.jmgm.2017.09.019
Abstrakt: The voltage-gated KCNQ1/KCNE1 potassium ion channel complex, forms the slow delayed rectifier (I Ks ) current in the heart, which plays an important role in heart signaling. The importance of KCNQ1/KCNE1 channel's function is further implicated by the linkage between loss-of-function and gain-of-function mutations in KCNQ1 or KCNE1, and long QT syndromes, congenital atrial fibrillation, and short QT syndrome. Also, KCNQ1/KCNE1 channels are an off-target for many non-cardiovascular drugs, leading to fatal cardiac irregularities. One solution to address and study the mentioned aspects of KCNQ1/KNCE1 channel would be the structural studies using a validated and accurate model. Along the same line in this study, we have used several top-notch modeling approaches to build a structural model for the open state of KCNQ1 protein, which is both accurate and compatible with available experimental data. Next, we included the KCNE1 protein components using data-driven protein-protein docking simulations, encompassing a 4:2 stoichiometry to complete the picture of the channel complex formed by these two proteins. All the protein systems generated through these processes were refined by long Molecular Dynamics simulations. The refined models were analyzed extensively to infer data about the interaction of KCNQ1 channel with its accessory KCNE1 beta subunits.
(Copyright © 2017 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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