6MCK

p97 D1D2 with CB5083 bound

6MCK の概要

• エントリーDOI: 10.2210/pdb6mck/pdb
• 分子名称: 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)
• 機能のキーワード: vcp, p97, cb-5083, aaa atpase, anticancer, drug, chaperone, hydrolase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 12
• 化学式量合計: 811029.13

構造登録者

Xia, D.,Tang, W.K. (登録日: 2018-08-31, 公開日: 2019-01-23, 最終更新日: 2025-06-11)

主引用文献

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

実験手法

X-RAY DIFFRACTION (3.77 Å)