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      Simulating PIP 2-Induced Gating Transitions in Kir6.2 Channels

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          Abstract

          ATP-sensitive potassium (K ATP) channels consist of an inwardly rectifying K + channel (Kir6.2) pore, to which four ATP-sensitive sulfonylurea receptor (SUR) domains are attached, thereby coupling K + permeation directly to the metabolic state of the cell. Dysfunction is linked to neonatal diabetes and other diseases. K + flux through these channels is controlled by conformational changes in the helix bundle region, which acts as a physical barrier for K + permeation. In addition, the G-loop, located in the cytoplasmic domain, and the selectivity filter might contribute to gating, as suggested by different disease-causing mutations. Gating of Kir channels is regulated by different ligands, like G βγ, H +, Na +, adenosine nucleotides, and the signaling lipid phosphatidyl-inositol 4,5-bisphosphate (PIP 2), which is an essential activator for all eukaryotic Kir family members. Although molecular determinants of PIP 2 activation of K ATP channels have been investigated in functional studies, structural information of the binding site is still lacking as PIP 2 could not be resolved in Kir6.2 cryo-EM structures. In this study, we used Molecular Dynamics (MD) simulations to examine the dynamics of residues associated with gating in Kir6.2. By combining this structural information with functional data, we investigated the mechanism underlying Kir6.2 channel regulation by PIP 2.

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              Matplotlib: A 2D Graphics Environment

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                Author and article information

                Contributors
                Journal
                Front Mol Biosci
                Front Mol Biosci
                Front. Mol. Biosci.
                Frontiers in Molecular Biosciences
                Frontiers Media S.A.
                2296-889X
                10 August 2021
                2021
                : 8
                Affiliations
                Department of Pharmaceutical Sciences, Division of Pharmacology and Toxicology, University of Vienna, Vienna, Austria
                Author notes

                Edited by: Lei Shi, National Institutes of Health (NIH), United States

                Reviewed by: Izhar Karbat, Weizmann Institute of Science, Israel

                Ralf Schmid, University of Leicester, United Kingdom

                *Correspondence: Anna Stary-Weinzinger, anna.stary@ 123456univie.ac.at

                This article was submitted to Structural Biology, a section of the journal Frontiers in Molecular Biosciences

                Article
                711975
                10.3389/fmolb.2021.711975
                8384051
                34447786
                f476a945-7a46-4d6d-8ffd-e8dfbd6be30f
                Copyright © 2021 Bründl, Pellikan and Stary-Weinzinger.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Funding
                Funded by: Austrian Science Fund 10.13039/501100002428
                Award ID: W1232
                Categories
                Molecular Biosciences
                Original Research

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