3TPX

Crystal structure of human MDM2 in complex with a trifluoromethylated D-peptide inhibitor

3TPX の概要

• エントリーDOI: 10.2210/pdb3tpx/pdb
• 関連するPDBエントリー: 3EQS 3IUX 3IWY 3LNJ 3LNZ
• 関連するBIRD辞書のPRD_ID: PRD_000995
• 分子名称: E3 ubiquitin-protein ligase Mdm2, D-peptide inhibitor DPMI-delta, SULFATE ION, ... (6 entities in total)
• 機能のキーワード: ligase-ligase inhibitor complex, mdm2-d-peptide inhibitor complex, p53-binding domain of mdm2-d-peptide inhibitor complex, ligase/ligase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Nucleus, nucleoplasm: Q00987
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 35578.48

構造登録者

Wu, X.,Pazgier, M. (登録日: 2011-09-08, 公開日: 2012-06-20, 最終更新日: 2023-12-06)

主引用文献

Zhan, C.,Zhao, L.,Wei, X.,Wu, X.,Chen, X.,Yuan, W.,Lu, W.Y.,Pazgier, M.,Lu, W.
An Ultrahigh Affinity d-Peptide Antagonist Of MDM2.
J.Med.Chem., 55:6237-6241, 2012

PubMed Abstract: The oncoprotein MDM2 negatively regulates the activity and stability of the p53 tumor suppressor and is an important molecular target for anticancer therapy. Aided by mirror image phage display and native chemical ligation, we have previously discovered several proteolysis-resistant duodecimal d-peptide antagonists of MDM2, termed (D)PMI-α, β, γ. The prototypic d-peptide inhibitor (D)PMI-α binds ((25-109))MDM2 at an affinity of 220 nM and kills tumor cells in vitro and inhibits tumor growth in vivo by reactivating the p53 pathway. Herein, we report the design of a superactive d-peptide antagonist of MDM2, termed (D)PMI-δ, of which the binding affinity for ((25-109))MDM2 has been improved over (D)PMI-α by 3 orders of magnitude (K(d) = 220 pM). X-ray crystallographic studies validate (D)PMI-δ as an exceedingly potent inhibitor of the p53-MDM2 interaction, promising to be a highly attractive lead drug candidate for anticancer therapeutic development.

PubMed: 22694121
DOI: 10.1021/jm3005465

実験手法

X-RAY DIFFRACTION (1.8 Å)