2V1Y

Structure of a phosphoinositide 3-kinase alpha adaptor-binding domain (ABD) in a complex with the iSH2 domain from p85 alpha

Summary for 2V1Y

• Entry DOI: 10.2210/pdb2v1y/pdb
• Related: 1A0N 1AZG 1H9O 1PBW 1PHT 1PIC 1PKS 1PKT 2IUG 2IUH 2IUI
• Descriptor: PHOSPHATIDYLINOSITOL-4,5-BISPHOSPHATE 3-KINASE CATALYTIC SUBUNIT ALPHA ISOFORM, PHOSPHATIDYLINOSITOL 3-KINASE REGULATORY SUBUNIT ALPHA (3 entities in total)
• Functional Keywords: kinase, cancer, sh2 domain, sh3 domain, transferase, oncogenic mutations, host-virus interaction, phosphorylation, disease mutation, phosphoinositide, phospholipid, phospholipid signalling, phosphoinositide 3-kinase, signal transduction
• Biological source: BOS TAURUS (BOVINE); More
• Total number of polymer chains: 2
• Total formula weight: 34044.88

Authors

Miled, N.,Yan, Y.,Hon, W.C.,Perisic, O.,Zvelebil, M.,Inbar, Y.,Schneidman-Duhovny, D.,Wolfson, H.J.,Backer, J.M.,Williams, R.L. (deposition date: 2007-05-30, release date: 2007-07-24, Last modification date: 2024-11-20)

Primary citation

Miled, N.,Yan, Y.,Hon, W.C.,Perisic, O.,Zvelebil, M.,Inbar, Y.,Schneidman-Duhovny, D.,Wolfson, H.J.,Backer, J.M.,Williams, R.L.
Mechanism of Two Classes of Cancer Mutations in the Phosphoinositide 3-Kinase Catalytic Subunit.
Science, 317:239-, 2007

PubMed Abstract: Many human cancers involve up-regulation of the phosphoinositide 3-kinase PI3Kalpha, with oncogenic mutations identified in both the p110alpha catalytic and the p85alpha regulatory subunits. We used crystallographic and biochemical approaches to gain insight into activating mutations in two noncatalytic p110alpha domains-the adaptor-binding and the helical domains. A structure of the adaptor-binding domain of p110alpha in a complex with the p85alpha inter-Src homology 2 (inter-SH2) domain shows that oncogenic mutations in the adaptor-binding domain are not at the inter-SH2 interface but in a polar surface patch that is a plausible docking site for other domains in the holo p110/p85 complex. We also examined helical domain mutations and found that the Glu545 to Lys545 (E545K) oncogenic mutant disrupts an inhibitory charge-charge interaction with the p85 N-terminal SH2 domain. These studies extend our understanding of the architecture of PI3Ks and provide insight into how two classes of mutations that cause a gain in function can lead to cancer.

PubMed: 17626883
DOI: 10.1126/SCIENCE.1135394

Experimental method

X-RAY DIFFRACTION (2.4 Å)