5IZ9

Protein-protein interaction

Summary for 5IZ9

• Entry DOI: 10.2210/pdb5iz9/pdb
• Related: 5IZ6 5IZ8 5IZA
• Descriptor: Adenomatous polyposis coli protein, ACE-GLY-GLY-GLU-ALA-LEU-ALA-ASP-NH2 (3 entities in total)
• Functional Keywords: apc, asef, colon cancer, drug discovery, protein binding-inhibitor complex, protein binding/inhibitor
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 39923.92

Authors

Zhao, Y.,Jiang, H.,Yang, X.,Jiang, F.,Song, K.,Zhang, J. (deposition date: 2016-03-25, release date: 2017-07-05, Last modification date: 2024-10-30)

Primary citation

Jiang, H.,Deng, R.,Yang, X.,Shang, J.,Lu, S.,Zhao, Y.,Song, K.,Liu, X.,Zhang, Q.,Chen, Y.,Chinn, Y.E.,Wu, G.,Li, J.,Chen, G.,Yu, J.,Zhang, J.
Peptidomimetic inhibitors of APC-Asef interaction block colorectal cancer migration.
Nat. Chem. Biol., 13:994-1001, 2017

PubMed Abstract: The binding of adenomatous polyposis coli (APC) to its receptor Asef relieves the negative intramolecular regulation of Asef and leads to aberrant cell migration in human colorectal cancer. Because of its crucial role in metastatic dissemination, the interaction between APC and Asef is an attractive target for anti-colorectal-cancer therapy. We rationally designed a series of peptidomimetics that act as potent inhibitors of the APC interface. Crystal structures and biochemical and cellular assays showed that the peptidomimetics in the APC pocket inhibited the migration of colorectal cells by disrupting APC-Asef interaction. By using the peptidomimetic inhibitor as a chemical probe, we found that CDC42 was the downstream GTPase involved in APC-stimulated Asef activation in colorectal cancer cells. Our work demonstrates the feasibility of exploiting APC-Asef interaction to regulate the migration of colorectal cancer cells, and provides what to our knowledge is the first class of protein-protein interaction inhibitors available for the development of cancer therapeutics targeting APC-Asef signaling.

PubMed: 28759015
DOI: 10.1038/nchembio.2442

Experimental method

X-RAY DIFFRACTION (2.93 Å)