5sxa
Crystal Structure of PI3Kalpha in complex with fragment 10
Structural highlights
FunctionP85A_HUMAN Binds to activated (phosphorylated) protein-Tyr kinases, through its SH2 domain, and acts as an adapter, mediating the association of the p110 catalytic unit to the plasma membrane. Necessary for the insulin-stimulated increase in glucose uptake and glycogen synthesis in insulin-sensitive tissues. Plays an important role in signaling in response to FGFR1, FGFR2, FGFR3, FGFR4, KITLG/SCF, KIT, PDGFRA and PDGFRB. Likewise, plays a role in ITGB2 signaling.[1] [2] [3] Publication Abstract from PubMedPIK3CA, the gene that encodes the catalytic subunit of phosphatidylinositol 3-kinase alpha (PI3Kalpha), is frequently mutated in breast and other types of cancer. A specific inhibitor that targets the mutant forms of PI3Kalpha could maximize treatment efficiency while minimizing side-effects. Herein we describe the identification of novel binding pockets that may provide an opportunity for the design of mutant selective inhibitors. Using a fragment-based approach, we screened a library of 352 fragments (MW<300Da) for binding to PI3Kalpha by X-ray crystallography. Five novel binding pockets were identified, each providing potential opportunities for inhibitor design. Of particular interest was a binding pocket near Glu542, which is located in one of the two most frequently mutated domains. Identification of allosteric binding sites for PI3Kalpha oncogenic mutant specific inhibitor design.,Miller MS, Maheshwari S, McRobb FM, Kinzler KW, Amzel LM, Vogelstein B, Gabelli SB Bioorg Med Chem. 2017 Feb 15;25(4):1481-1486. doi: 10.1016/j.bmc.2017.01.012., Epub 2017 Jan 16. PMID:28129991[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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