{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T21:56:04Z","timestamp":1773179764902,"version":"3.50.1"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1010859","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2023,2,2]],"date-time":"2023-02-02T00:00:00Z","timestamp":1675296000000}}],"reference-count":46,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2023,1,23]],"date-time":"2023-01-23T00:00:00Z","timestamp":1674432000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010665","name":"H2020 Marie Sk\u0142odowska-Curie Actions","doi-asserted-by":"publisher","award":["813239"],"award-info":[{"award-number":["813239"]}],"id":[{"id":"10.13039\/100010665","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010665","name":"H2020 Marie Sk\u0142odowska-Curie Actions","doi-asserted-by":"publisher","award":["813239"],"award-info":[{"award-number":["813239"]}],"id":[{"id":"10.13039\/100010665","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>RNA recognition motifs (RRM) are the most prevalent class of RNA binding domains in eucaryotes. Their RNA binding preferences have been investigated for almost two decades, and even though some RRM domains are now very well described, their RNA recognition code has remained elusive. An increasing number of experimental structures of RRM-RNA complexes has become available in recent years. Here, we perform an in-depth computational analysis to derive an RNA recognition code for canonical RRMs. We present and validate a computational scoring method to estimate the binding between an RRM and a single stranded RNA, based on structural data from a carefully curated multiple sequence alignment, which can predict RRM binding RNA sequence motifs based on the RRM protein sequence. Given the importance and prevalence of RRMs in humans and other species, this tool could help design RNA binding motifs with uses in medical or synthetic biology applications, leading towards the <jats:italic>de novo<\/jats:italic> design of RRMs with specific RNA recognition.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1010859","type":"journal-article","created":{"date-parts":[[2023,1,23]],"date-time":"2023-01-23T18:40:40Z","timestamp":1674499240000},"page":"e1010859","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":20,"title":["Deciphering the RRM-RNA recognition code: A computational analysis"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4313-3845","authenticated-orcid":true,"given":"Joel","family":"Roca-Mart\u00ednez","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7025-2241","authenticated-orcid":true,"given":"Hrishikesh","family":"Dhondge","sequence":"additional","affiliation":[]},{"given":"Michael","family":"Sattler","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7470-4324","authenticated-orcid":true,"given":"Wim F.","family":"Vranken","sequence":"additional","affiliation":[]}],"member":"340","published-online":{"date-parts":[[2023,1,23]]},"reference":[{"key":"pcbi.1010859.ref001","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1016\/j.sbi.2008.04.002","article-title":"RNA recognition motifs: boring? 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Huang","year":"2010","journal-title":"Bioinformatics"},{"key":"pcbi.1010859.ref034","doi-asserted-by":"crossref","first-page":"2295","DOI":"10.1093\/nar\/gkn072","article-title":"PROMALS3D: a tool for multiple protein sequence and structure alignments","volume":"36","author":"J Pei","year":"2008","journal-title":"Nucleic Acids Res"},{"key":"pcbi.1010859.ref035","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1007\/978-1-4939-6406-2_2","article-title":"The GOR Method of Protein Secondary Structure Prediction and Its Application as a Protein Aggregation Prediction Tool","volume":"1484","author":"M Kouza","year":"2017","journal-title":"Methods Mol Biol"},{"key":"pcbi.1010859.ref036","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1016\/S0076-6879(96)66034-0","article-title":"GOR method for predicting protein secondary structure from amino acid sequence","volume":"266","author":"J Garnier","year":"1996","journal-title":"Methods 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