5SX9

Crystal Structure of PI3Kalpha in complex with fragment 14

Summary for 5SX9

• Entry DOI: 10.2210/pdb5sx9/pdb
• Related: 5SW8 5SWG 5SWO 5SWP 5SWR 5SWT 5SX8 5SXA 5SXB 5SXC 5SXD 5SXE 5SXF 5SXI 5SXJ 5SXK
• Descriptor: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform, Phosphatidylinositol 3-kinase regulatory subunit alpha, 4,6-dimethylpyridin-2-amine (3 entities in total)
• Functional Keywords: lipid kinase, phosphoinositide, 3-kinase, signaling, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 161691.68

Authors

Gabelli, S.B.,Vogelstein, B.,Miller, M.S.,Amzel, L.M. (deposition date: 2016-08-09, release date: 2017-02-15, Last modification date: 2024-10-09)

Primary citation

Miller, M.S.,Maheshwari, S.,McRobb, F.M.,Kinzler, K.W.,Amzel, L.M.,Vogelstein, B.,Gabelli, S.B.
Identification of allosteric binding sites for PI3K alpha oncogenic mutant specific inhibitor design.
Bioorg. Med. Chem., 25:1481-1486, 2017

PubMed Abstract: PIK3CA, the gene that encodes the catalytic subunit of phosphatidylinositol 3-kinase α (PI3Kα), is frequently mutated in breast and other types of cancer. A specific inhibitor that targets the mutant forms of PI3Kα 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 PI3Kα 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.

PubMed: 28129991
DOI: 10.1016/j.bmc.2017.01.012

Experimental method

X-RAY DIFFRACTION (3.52 Å)