6MCK

p97 D1D2 with CB5083 bound

Summary for 6MCK

• Entry DOI: 10.2210/pdb6mck/pdb
• Descriptor: Transitional endoplasmic reticulum ATPase, 1-[4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl]-2-methyl-1H-indole-4-carboxamide (3 entities in total)
• Functional Keywords: vcp, p97, cb-5083, aaa atpase, anticancer, drug, chaperone, hydrolase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 12
• Total formula weight: 811029.13

Authors

Xia, D.,Tang, W.K. (deposition date: 2018-08-31, release date: 2019-01-23, Last modification date: 2025-06-11)

Primary citation

Tang, W.K.,Odzorig, T.,Jin, W.,Xia, D.
Structural Basis of p97 Inhibition by the Site-Selective Anticancer Compound CB-5083.
Mol. Pharmacol., 95:286-293, 2019

PubMed Abstract: Inhibition of p97, a key player in the ubiquitin-proteasome degradation pathway, has been proposed as a treatment of cancer. This concept was nearly realized recently when a potent p97 inhibitor, 1-[4-(benzylamino)-5H,7H,8H-pyrano[4,3-d]pyrimidin-2-yl]-2-methyl-1H-indole-4-carboxamide (CB-5083), was developed and demonstrated broad antitumor activity in various tumor models. CB-5083 functions as a competitive inhibitor that binds selectively to the ATP-binding site of the D2 domain, although both the D1 and D2 ATPase sites of p97 are highly similar. Despite its promising anticancer activity, CB-5083 failed its phase I clinical trials due to an unexpected off-target effect, which necessitates further improvement of the inhibitor. In this study, we determined the crystal structure of N-terminal domain-truncated p97 in complex with CB-5083. It provides a structural basis for the specificity of CB-5083 toward the D2 domain, offers an explanation in atomic detail for the mutations that confer resistance to CB-5083, and establishes a foundation for future structure-guided efforts to develop the next generation of p97 inhibitors.

PubMed: 30591537
DOI: 10.1124/mol.118.114256

Experimental method

X-RAY DIFFRACTION (3.77 Å)