{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T02:40:57Z","timestamp":1760236857487,"version":"build-2065373602"},"reference-count":57,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2021,12,29]],"date-time":"2021-12-29T00:00:00Z","timestamp":1640736000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Servier (France)","award":["# 45367"],"award-info":[{"award-number":["# 45367"]}]},{"name":"AFM-telethon","award":["(#19928 and #23207"],"award-info":[{"award-number":["(#19928 and #23207"]}]},{"name":"ANR-CNRS","award":["cacsice"],"award-info":[{"award-number":["cacsice"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>ATP-sensitive potassium (K-ATP) channels are ubiquitously expressed on the plasma membrane of cells in several organs, including the heart, pancreas, and brain, and they govern a wide range of physiological processes. In pancreatic \u03b2-cells, K-ATP channels composed of Kir6.2 and SUR1 play a key role in coupling blood glucose and insulin secretion. A tryptophan residue located at the cytosolic end of the transmembrane helix is highly conserved in eukaryote and prokaryote Kir channels. Any mutation on this amino acid causes a gain of function and neonatal diabetes mellitus. In this study, we have investigated the effect of mutation on this highly conserved residue on a KirBac channel (prokaryotic homolog of mammalian Kir6.2). We provide the crystal structure of the mutant KirBac3.1 W46R (equivalent to W68R in Kir6.2) and its conformational flexibility properties using HDX-MS. In addition, the detailed dynamical view of the mutant during the gating was investigated using the in silico method. Finally, functional assays have been performed. A comparison of important structural determinants for the gating mechanism between the wild type KirBac and the mutant W46R suggests interesting structural and dynamical clues and a mechanism of action of the mutation that leads to the gain of function.<\/jats:p>","DOI":"10.3390\/ijms23010335","type":"journal-article","created":{"date-parts":[[2021,12,29]],"date-time":"2021-12-29T02:31:27Z","timestamp":1640745087000},"page":"335","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrative Study of the Structural and Dynamical Properties of a KirBac3.1 Mutant: Functional Implication of a Highly Conserved Tryptophan in the Transmembrane Domain"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3308-631X","authenticated-orcid":false,"given":"Charline","family":"Fagnen","sequence":"first","affiliation":[{"name":"IMPMC, UMR 7590, CNRS, Mus\u00e9um National d\u2019Histoire Naturelle, Sorbonne Universit\u00e9, 75005 Paris, France"},{"name":"Laboratoire de Biologie et Pharmacologie Appliqu\u00e9e, Ecole Normale Sup\u00e9rieure Paris-Saclay, 4 Ave. des Sciences, 91190 Gif-sur-Yvette, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ludovic","family":"Bannwarth","sequence":"additional","affiliation":[{"name":"IMPMC, UMR 7590, CNRS, Mus\u00e9um National d\u2019Histoire Naturelle, Sorbonne Universit\u00e9, 75005 Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Iman","family":"Oubella","sequence":"additional","affiliation":[{"name":"IMPMC, UMR 7590, CNRS, Mus\u00e9um National d\u2019Histoire Naturelle, Sorbonne Universit\u00e9, 75005 Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dania","family":"Zuniga","sequence":"additional","affiliation":[{"name":"IMPMC, UMR 7590, CNRS, Mus\u00e9um National d\u2019Histoire Naturelle, Sorbonne Universit\u00e9, 75005 Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1196-1635","authenticated-orcid":false,"given":"Ahmed","family":"Haouz","sequence":"additional","affiliation":[{"name":"Institut Pasteur, C2RT-Plate-Forme de Cristallographie CNRS-UMR3528, 75724 Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric","family":"Forest","sequence":"additional","affiliation":[{"name":"CNRS, IBS, CEA, University Grenoble Alpes, 38044 Grenoble, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rosa","family":"Scala","sequence":"additional","affiliation":[{"name":"CNRS UMR7370, LP2M, Labex ICST, Facult\u00e9 de M\u00e9decine, University C\u00f4te d\u2019Azur, 06560 Nice, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sa\u00efd","family":"Bendahhou","sequence":"additional","affiliation":[{"name":"CNRS UMR7370, LP2M, Labex ICST, Facult\u00e9 de M\u00e9decine, University C\u00f4te d\u2019Azur, 06560 Nice, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7001-7498","authenticated-orcid":false,"given":"Rita","family":"De Zorzi","sequence":"additional","affiliation":[{"name":"Department of Chemical and Pharmaceutical Sciences, University of Trieste, Via Licio Giorgeri 1, 34127 Trieste, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7480-3349","authenticated-orcid":false,"given":"David","family":"Perahia","sequence":"additional","affiliation":[{"name":"Laboratoire de Biologie et Pharmacologie Appliqu\u00e9e, Ecole Normale Sup\u00e9rieure Paris-Saclay, 4 Ave. des Sciences, 91190 Gif-sur-Yvette, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Catherine","family":"V\u00e9nien-Bryan","sequence":"additional","affiliation":[{"name":"IMPMC, UMR 7590, CNRS, Mus\u00e9um National d\u2019Histoire Naturelle, Sorbonne Universit\u00e9, 75005 Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,29]]},"reference":[{"key":"ref_1","first-page":"101","article-title":"Molecular biology of adenosine triphosphate-sensitive potassium channels","volume":"20","author":"Bryan","year":"1999","journal-title":"Endocr. 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