{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T06:10:22Z","timestamp":1772172622599,"version":"3.50.1"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1008426","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,3,25]],"date-time":"2021-03-25T00:00:00Z","timestamp":1616630400000}}],"reference-count":42,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2021,3,15]],"date-time":"2021-03-15T00:00:00Z","timestamp":1615766400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005876","name":"Biotieteiden ja Ymp\u00e4rist\u00f6n Tutkimuksen Toimikunta","doi-asserted-by":"publisher","award":["298863"],"award-info":[{"award-number":["298863"]}],"id":[{"id":"10.13039\/501100005876","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>\n                    Lecithin:cholesterol acyltransferase protein (LCAT) promotes the esterification reaction between cholesterol and phospholipid-derived acyl chains. Positive allosteric modulators have been developed to treat LCAT deficiencies and, plausibly, also cardiovascular diseases in the future. The mechanism of action of these compounds is poorly understood. Here computational docking and atomistic molecular dynamics simulations were utilized to study the interactions between LCAT and the activating compounds. Results indicate that all drugs bind to the allosteric binding pocket in the membrane-binding domain in a similar fashion. The presence of the compounds in the allosteric site results in a distinct spatial orientation and sampling of the membrane-binding domain (MBD). The MBD\u2019s different spatial arrangement plausibly affects the lid\u2019s movement from closed to open state and\n                    <jats:italic>vice versa<\/jats:italic>\n                    , as suggested by steered molecular dynamics simulations.\n                  <\/jats:p>","DOI":"10.1371\/journal.pcbi.1008426","type":"journal-article","created":{"date-parts":[[2021,3,15]],"date-time":"2021-03-15T13:38:59Z","timestamp":1615815539000},"page":"e1008426","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":6,"title":["Positive allosteric modulators of lecithin: Cholesterol acyltransferase adjust the orientation of the membrane-binding domain and alter its spatial free energy profile"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8679-3712","authenticated-orcid":true,"given":"Akseli","family":"Niemel\u00e4","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3979-7809","authenticated-orcid":true,"given":"Artturi","family":"Koivuniemi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2021,3,15]]},"reference":[{"issue":"12","key":"pcbi.1008426.ref001","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.1161\/01.RES.0000170946.56981.5c","article-title":"New Insights Into the Regulation of HDL Metabolism and Reverse Cholesterol Transport","volume":"96","author":"GF Lewis","year":"2005","journal-title":"Circ Res"},{"issue":"2","key":"pcbi.1008426.ref002","doi-asserted-by":"crossref","first-page":"E248","DOI":"10.1210\/jc.2011-1846","article-title":"LCAT, HDL Cholesterol, and Ischemic Cardiovascular Disease: A Mendelian Randomization Study of HDL Cholesterol in 54,500 Individuals","volume":"97","author":"CL Haase","year":"2012","journal-title":"J Clin Endocrinol Metab"},{"issue":"9943","key":"pcbi.1008426.ref003","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1016\/S0140-6736(14)61217-4","article-title":"HDL and cardiovascular disease","volume":"384","author":"DJ Rader","year":"2014","journal-title":"Lancet"},{"issue":"2","key":"pcbi.1008426.ref004","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/j.ajhg.2014.01.009","article-title":"Association of low-frequency and rare coding-sequence variants with blood lipids and coronary heart disease in 56,000 whites and blacks","volume":"94","author":"GM Peloso","year":"2014","journal-title":"Am J Hum Genet"},{"issue":"8149","key":"pcbi.1008426.ref005","first-page":"922","article-title":"Fish-eye disease. 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