{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T22:03:06Z","timestamp":1775080986573,"version":"3.50.1"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1007597","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2020,11,9]],"date-time":"2020-11-09T00:00:00Z","timestamp":1604880000000}}],"reference-count":45,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2020,10,28]],"date-time":"2020-10-28T00:00:00Z","timestamp":1603843200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"\n As sequencing methodologies continue to advance, the availability of protein sequences far outpaces the ability of structure determination. Homology modeling is used to bridge this gap but relies on high-identity templates for accurate model building. G-protein coupled receptors (GPCRs) represent a significant target class for pharmaceutical therapies in which homology modeling could fill the knowledge gap for structure-based drug design. To date, only about 17% of druggable GPCRs have had their structures characterized at atomic resolution. However, modeling of the remaining 83% is hindered by the low sequence identity between receptors. Here we test key inputs in the model building process using GPCRs as a focus to improve the pipeline in two critical ways: Firstly, we use a blended sequence- and structure-based alignment that accounts for structure conservation in loop regions. Secondly, by merging multiple template structures into one comparative model, the best possible template for every region of a target can be used expanding the conformational space sampled in a meaningful way. This optimization allows for accurate modeling of receptors using templates as low as 20% sequence identity, which accounts for nearly the entire druggable space of GPCRs. A model database of all non-odorant GPCRs is made available at\n www.rosettagpcr.org<\/jats:ext-link>\n . Additionally, all protocols are made available with insights into modifications that may improve accuracy at new targets.\n <\/jats:p>","DOI":"10.1371\/journal.pcbi.1007597","type":"journal-article","created":{"date-parts":[[2020,10,28]],"date-time":"2020-10-28T13:54:08Z","timestamp":1603893248000},"page":"e1007597","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":40,"title":["Improving homology modeling from low-sequence identity templates in Rosetta: A case study in GPCRs"],"prefix":"10.1371","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9251-9480","authenticated-orcid":true,"given":"Brian Joseph","family":"Bender","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6811-9951","authenticated-orcid":true,"given":"Brennica","family":"Marlow","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8945-193X","authenticated-orcid":true,"given":"Jens","family":"Meiler","sequence":"additional","affiliation":[]}],"member":"340","published-online":{"date-parts":[[2020,10,28]]},"reference":[{"key":"pcbi.1007597.ref001","article-title":"The G-protein-coupled receptors in the human genome form five main families. 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