8AM0
Crystal structure of human T1061E PI3Kalpha in complex with its regulatory subunit and the inhibitor GDC-0077 (Inavolisib)
Summary for 8AM0
| Entry DOI | 10.2210/pdb8am0/pdb |
| Descriptor | Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform, Isoform 3 of Phosphatidylinositol 3-kinase regulatory subunit alpha, (2R)-2-[[2-[(4S)-4-[bis(fluoranyl)methyl]-2-oxidanylidene-1,3-oxazolidin-3-yl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepin-9-yl]amino]propanamide, ... (7 entities in total) |
| Functional Keywords | lipid kinase, phosphoinositide, 3-kinase, signaling, transferase |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 2 |
| Total formula weight | 160453.96 |
| Authors | Goncalves, M.,Johnson, J.L.,Roewer, K.M. (deposition date: 2022-08-02, release date: 2023-12-13, Last modification date: 2024-01-03) |
| Primary citation | Lin, T.Y.,Ramsamooj, S.,Perrier, T.,Liberatore, K.,Lantier, L.,Vasan, N.,Karukurichi, K.,Hwang, S.K.,Kesicki, E.A.,Kastenhuber, E.R.,Wiederhold, T.,Yaron, T.M.,Huntsman, E.M.,Zhu, M.,Ma, Y.,Paddock, M.N.,Zhang, G.,Hopkins, B.D.,McGuinness, O.,Schwartz, R.E.,Ersoy, B.A.,Cantley, L.C.,Johnson, J.L.,Goncalves, M.D. Epinephrine inhibits PI3K alpha via the Hippo kinases. Cell Rep, 42:113535-113535, 2023 Cited by PubMed Abstract: The phosphoinositide 3-kinase p110α is an essential mediator of insulin signaling and glucose homeostasis. We interrogated the human serine, threonine, and tyrosine kinome to search for novel regulators of p110α and found that the Hippo kinases phosphorylate p110α at T1061, which inhibits its activity. This inhibitory state corresponds to a conformational change of a membrane-binding domain on p110α, which impairs its ability to engage membranes. In human primary hepatocytes, cancer cell lines, and rodent tissues, activation of the Hippo kinases MST1/2 using forskolin or epinephrine is associated with phosphorylation of T1061 and inhibition of p110α, impairment of downstream insulin signaling, and suppression of glycolysis and glycogen synthesis. These changes are abrogated when MST1/2 are genetically deleted or inhibited with small molecules or if the T1061 is mutated to alanine. Our study defines an inhibitory pathway of PI3K signaling and a link between epinephrine and insulin signaling. PubMed: 38060450DOI: 10.1016/j.celrep.2023.113535 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.818 Å) |
Structure validation
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