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Using a combined biochemical\/biophysical approach, we have revealed insight into regulation of kinase activity, specifically defining how immunodeficiency and oncogenic mutations of R1021 in the C-terminus can inactivate or activate enzyme activity. Screening of inhibitors using HDX-MS revealed that activation loop-binding inhibitors induce allosteric conformational changes that mimic those in the R1021C mutant. Structural analysis of advanced PI3K inhibitors in clinical development revealed novel binding pockets that can be exploited for further therapeutic development. Overall, this work provides unique insights into regulatory mechanisms that control PI3K\u03b3 kinase activity and shows a framework for the design of PI3K isoform and mutant selective inhibitors.<\/jats:p>","DOI":"10.7554\/elife.64691","type":"journal-article","created":{"date-parts":[[2021,3,4]],"date-time":"2021-03-04T08:01:47Z","timestamp":1614844907000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.64691","source":"Crossref","is-referenced-by-count":49,"title":["Disease-related mutations in PI3K\u03b3 disrupt regulatory C-terminal dynamics and reveal a path to selective inhibitors"],"prefix":"10.7554","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5909-4353","authenticated-orcid":true,"given":"Manoj K","family":"Rathinaswamy","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Microbiology, University of Victoria, Victoria, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zied","family":"Gaieb","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of California San Diego, San Diego, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaelin D","family":"Fleming","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Microbiology, University of Victoria, Victoria, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4688-8362","authenticated-orcid":true,"given":"Chiara","family":"Borsari","sequence":"additional","affiliation":[{"name":"University of Basel, Department of Biomedicine, Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noah J","family":"Harris","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Microbiology, University of Victoria, Victoria, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brandon E","family":"Moeller","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Microbiology, University of Victoria, Victoria, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3349-4281","authenticated-orcid":true,"given":"Matthias P","family":"Wymann","sequence":"additional","affiliation":[{"name":"University of Basel, Department of Biomedicine, Basel, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rommie E","family":"Amaro","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, University of California San Diego, San Diego, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7904-9859","authenticated-orcid":true,"given":"John E","family":"Burke","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Microbiology, University of Victoria, Victoria, Canada"},{"name":"Department of Biochemistry and Molecular Biology, The University of British Columbia, Vancouver, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4374","published-online":{"date-parts":[[2021,3,4]]},"reference":[{"key":"bib1","doi-asserted-by":"publisher","first-page":"818","DOI":"10.1158\/2159-8290.CD-17-0151","article-title":"AACR project GENIE: powering precision medicine through an international consortium","volume":"7","author":"AACR Project GENIE Consortium","year":"2017","journal-title":"Cancer Discov. 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