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Potent clinical inhibitors of HIV\u20101 protease show several orders of magnitude worse inhibition of highly drug\u2010resistant variants. Hence, the structure and enzyme activities were analyzed for HIV protease mutant HIV\u20101 protease (<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.chem.qmul.ac.uk\/iubmb\/enzyme\/EC3\/4\/23\/16.html\">EC\u00a03.4.23.16<\/jats:ext-link>) (PR) with 22 mutations (PRS5B) from a clinical isolate that was selected by machine learning to represent high\u2010level drug\u2010resistance. PRS5B has 22 mutations including only one (I84V) in the inhibitor binding site; however, clinical inhibitors had poor inhibition of PRS5B activity with kinetic inhibition value (<jats:italic>K<jats:sub>i<\/jats:sub><\/jats:italic>) values of 4\u20131000\u00a0n<jats:sc>m<\/jats:sc> or 18\u2010 to 8000\u2010fold worse than for wild\u2010type PR. High\u2010resolution crystal structures of PRS5B complexes with the best inhibitors, amprenavir (APV) and darunavir (DRV) (<jats:italic>K<jats:sub>i<\/jats:sub><\/jats:italic> ~\u00a04\u00a0n<jats:sc>m<\/jats:sc>), revealed only minor changes in protease\u2010inhibitor interactions. Instead, two distinct clusters of mutations in distal regions induce coordinated conformational changes that decrease favorable internal interactions across the entire protein subunit. The largest structural rearrangements are described and compared to other characterized resistant mutants. In the protease hinge region, the N83D mutation eliminates a hydrogen bond connecting the hinge and core of the protease and increases disorder compared to highly resistant mutants PR with 17 mutations and PR with 20 mutations with similar hinge mutations. In a distal \u03b2\u2010sheet, mutations G73T and A71V coordinate with accessory mutations to bring about shifts that propagate throughout the subunit. Molecular dynamics simulations of ligand\u2010free dimers show differences consistent with loss of interactions in mutant compared to wild\u2010type PR. Clusters of mutations exhibit both coordinated and antagonistic effects, suggesting PRS5B may represent an intermediate stage in the evolution of more highly resistant variants.<\/jats:p><\/jats:sec><jats:sec><jats:title>Databases<\/jats:title><jats:p>Structural data are available in Protein Data Bank under the accession codes <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.rcsb.org\/pdb\/search\/structidSearch.do?structureId=6P9A\">6P9A<\/jats:ext-link> and <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.rcsb.org\/pdb\/search\/structidSearch.do?structureId=6P9B\">6P9B<\/jats:ext-link> for PRS5B\/DRV and PRS5B\/APV, respectively.<\/jats:p><\/jats:sec>","DOI":"10.1111\/febs.15207","type":"journal-article","created":{"date-parts":[[2020,1,10]],"date-time":"2020-01-10T05:42:20Z","timestamp":1578634940000},"page":"3235-3254","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Highly drug\u2010resistant HIV\u20101 protease reveals decreased intra\u2010subunit interactions due to clusters of mutations"],"prefix":"10.1111","volume":"287","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5416-5789","authenticated-orcid":false,"given":"Daniel W.","family":"Kneller","sequence":"first","affiliation":[{"name":"Department of Biology Georgia State University Atlanta GA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3053-5677","authenticated-orcid":false,"given":"Johnson","family":"Agniswamy","sequence":"additional","affiliation":[{"name":"Department of Biology Georgia State University 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