PT  - JOURNAL ARTICLE
AU  - Rathinaswamy, Manoj K
AU  - Gaieb, Zied
AU  - Fleming, Kaelin D
AU  - Borsari, Chiara
AU  - Harris, Noah J
AU  - Moeller, Brandon E
AU  - Wymann, Matthias P
AU  - Amaro, Rommie E
AU  - Burke, John E
TI  - Disease related mutations in PI3Kγ disrupt regulatory C-terminal dynamics and reveals a path to selective inhibitors
AID  - 10.1101/2020.12.01.406264
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.12.01.406264
4099  - http://biorxiv.org/content/early/2020/12/02/2020.12.01.406264.short
4100  - http://biorxiv.org/content/early/2020/12/02/2020.12.01.406264.full
AB  - Class I Phosphoinositide 3-kinases (PI3Ks) are master regulators of cellular functions, with the p110γ subunit playing a key role in immune signalling. PI3Kγ is a key factor in inflammatory diseases, and has been identified as a therapeutic target for cancers due to its immunomodulatory role. 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 small molecule inhibitors using HDX-MS revealed that activation loop binding inhibitors induce allosteric conformational changes that mimic those seen for the R1021C mutant. Structural analysis of clinically advanced PI3K inhibitors revealed novel binding pockets that can be exploited for further therapeutic development. Overall this work provides unique insight into the regulatory mechanisms that control PI3Kγ kinase activity, and shows a framework for the design of PI3K isoform and mutant selective inhibitors.