{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Zhang M"],"funding":["CCR NIH HHS","NIH, National Cancer Institute, Center for Cancer Research","Intramural NIH HHS","NCI NIH HHS","National Cancer Institute, National Institutes of Health"],"pagination":["5849-5859"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC8916166"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["432(22)"],"pubmed_abstract":["PI3K lipid kinases signal through the PI3K/Akt pathway, regulating cell growth and proliferation. While the structural features that distinguish between the active and inactive states of protein kinases are well established, that has not been the case for lipid kinases, and neither was the structural mechanism controlling the switch between the two states. Class I PI3Ks are obligate heterodimers with catalytic and regulatory subunits. Here, we analyze PI3K crystal structures. Structures with the nSH2 (inactive state) are featured by collapsed activation loop (a-loop) and an IN kinase domain helix 11 (kα11). In the active state, the a-loop is extended and kα11 in the OUT conformation. Our analysis suggests that the nSH2 domain in the regulatory subunit regulates activation, catalysis and autoinhibition through the a-loop. Inhibition, activation and catalytic scenarios are shared by class IA PI3Ks; the activation is mimicked by oncogenic mutations and the inhibition offers an allosteric inhibitor strategy."],"journal":["Journal of molecular biology"],"pubmed_title":["Structural Features that Distinguish Inactive and Active PI3K Lipid Kinases."],"pmcid":["PMC8916166"],"funding_grant_id":["HHSN261200800001E","HHSN261200800001C","ZIA BC010440"],"pubmed_authors":["Jang H","Zhang M","Nussinov R"],"additional_accession":[]},"is_claimable":false,"name":"Structural Features that Distinguish Inactive and Active PI3K Lipid Kinases.","description":"PI3K lipid kinases signal through the PI3K/Akt pathway, regulating cell growth and proliferation. While the structural features that distinguish between the active and inactive states of protein kinases are well established, that has not been the case for lipid kinases, and neither was the structural mechanism controlling the switch between the two states. Class I PI3Ks are obligate heterodimers with catalytic and regulatory subunits. Here, we analyze PI3K crystal structures. Structures with the nSH2 (inactive state) are featured by collapsed activation loop (a-loop) and an IN kinase domain helix 11 (kα11). In the active state, the a-loop is extended and kα11 in the OUT conformation. Our analysis suggests that the nSH2 domain in the regulatory subunit regulates activation, catalysis and autoinhibition through the a-loop. Inhibition, activation and catalytic scenarios are shared by class IA PI3Ks; the activation is mimicked by oncogenic mutations and the inhibition offers an allosteric inhibitor strategy.","dates":{"release":"2020-01-01T00:00:00Z","publication":"2020 Nov","modification":"2026-05-30T15:49:46.109Z","creation":"2025-04-04T10:01:44.158Z"},"accession":"S-EPMC8916166","cross_references":{"pubmed":["32918948"],"doi":["10.1016/j.jmb.2020.09.002"]}}