4L23

Crystal Structure of p110alpha complexed with niSH2 of p85alpha and PI-103

Summary for 4L23

• Entry DOI: 10.2210/pdb4l23/pdb
• Related: 4L1B 4L2Y
• Descriptor: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform, Phosphatidylinositol 3-kinase regulatory subunit alpha, 3-(4-MORPHOLIN-4-YLPYRIDO[3',2':4,5]FURO[3,2-D]PYRIMIDIN-2-YL)PHENOL, ... (6 entities in total)
• Functional Keywords: atp binding, pi-103, signaling protein-transferase-inhibitor complex, signaling protein/transferase/inhibitor
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 164129.04

Authors

Zhang, J.,Zhao, Y.L.,Chen, Y.Y.,Huang, M.,Jiang, F. (deposition date: 2013-06-04, release date: 2014-01-01, Last modification date: 2024-02-28)

Primary citation

Zhao, Y.,Zhang, X.,Chen, Y.,Lu, S.,Peng, Y.,Wang, X.,Guo, C.,Zhou, A.,Zhang, J.,Luo, Y.,Shen, Q.,Ding, J.,Meng, L.,Zhang, J.
Crystal Structures of PI3K alpha Complexed with PI103 and Its Derivatives: New Directions for Inhibitors Design.
ACS Med Chem Lett, 5:138-142, 2014

PubMed Abstract: The phosphatidylinositol 3-kinase (PI3K) signaling pathway plays important roles in cell proliferation, growth, and survival. Hyperactivated PI3K is frequently found in a wide variety of human cancers, validating it as a promising target for cancer therapy. We determined the crystal structure of the human PI3Kα-PI103 complex to unravel molecular interactions. Based on the structure, substitution at the R1 position of the phenol portion of PI103 was demonstrated to improve binding affinity via forming a new H-bond with Lys802 at the bottom of the ATP catalytic site. Interestingly, the crystal structure of the PI3Kα-9d complex revealed that the flexibility of Lys802 can also induce additional space at the catalytic site for further modification. Thus, these crystal structures provide a molecular basis for the strong and specific interactions and demonstrate the important role of Lys802 in the design of novel PI3Kα inhibitors.

PubMed: 24900786
DOI: 10.1021/ml400378e

Experimental method

X-RAY DIFFRACTION (2.501 Å)