4OVU

Crystal Structure of p110alpha in complex with niSH2 of p85alpha

Summary for 4OVU

• Entry DOI: 10.2210/pdb4ovu/pdb
• Related: 4OVV
• Descriptor: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform, Phosphatidylinositol 3-kinase regulatory subunit alpha (3 entities in total)
• Functional Keywords: p110, p85, pi3kca, pi3k, pik3r1, phosphatidilynositol 3, 4, 5 triphosphate, pip2, phosphatidylinositol 4, 5 bisphosphate, lipid kinase, phosphoinositide, 3-kinase, signaling, phosphatidylinositol 3-kinase, transferase-transferase regulator complex, transferase/transferase regulator
• Biological source: Homo sapiens; More
• Total number of polymer chains: 2
• Total formula weight: 161489.54

Authors

Gabelli, S.B.,Vogelstein, B.,Miller, M.S.,Amzel, L.M. (deposition date: 2014-01-14, release date: 2014-09-03, Last modification date: 2023-09-27)

Primary citation

Miller, M.S.,Schmidt-Kittler, O.,Bolduc, D.M.,Brower, E.T.,Chaves-Moreira, D.,Allaire, M.,Kinzler, K.W.,Jennings, I.G.,Thompson, P.E.,Cole, P.A.,Amzel, L.M.,Vogelstein, B.,Gabelli, S.B.
Structural basis of nSH2 regulation and lipid binding in PI3K alpha.
Oncotarget, 5:5198-5208, 2014

PubMed Abstract: We report two crystal structures of the wild-type phosphatidylinositol 3-kinase α (PI3Kα) heterodimer refined to 2.9 Å and 3.4 Å resolution: the first as the free enzyme, the second in complex with the lipid substrate, diC4-PIP₂, respectively. The first structure shows key interactions of the N-terminal SH2 domain (nSH2) and iSH2 with the activation loop that suggest a mechanism by which the enzyme is inhibited in its basal state. In the second structure, the lipid substrate binds in a positively charged pocket adjacent to the ATP-binding site, bordered by the P-loop, the activation loop and the iSH2 domain. An additional lipid-binding site was identified at the interface of the ABD, iSH2 and kinase domains. The ability of PI3Kα to bind an additional PIP₂ molecule was confirmed in vitro by fluorescence quenching experiments. The crystal structures reveal key differences in the way the nSH2 domain interacts with wild-type p110α and with the oncogenic mutant p110αH1047R. Increased buried surface area and two unique salt-bridges observed only in the wild-type structure suggest tighter inhibition in the wild-type PI3Kα than in the oncogenic mutant. These differences may be partially responsible for the increased basal lipid kinase activity and increased membrane binding of the oncogenic mutant.

PubMed: 25105564

Experimental method

X-RAY DIFFRACTION (2.96 Å)