3TPX

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

Summary for 3TPX

• Entry DOI: 10.2210/pdb3tpx/pdb
• Related: 3EQS 3IUX 3IWY 3LNJ 3LNZ
• Related PRD ID: PRD_000995
• Descriptor: E3 ubiquitin-protein ligase Mdm2, D-peptide inhibitor DPMI-delta, SULFATE ION, ... (6 entities in total)
• Functional Keywords: ligase-ligase inhibitor complex, mdm2-d-peptide inhibitor complex, p53-binding domain of mdm2-d-peptide inhibitor complex, ligase/ligase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus, nucleoplasm: Q00987
• Total number of polymer chains: 6
• Total formula weight: 35578.48

Authors

Wu, X.,Pazgier, M. (deposition date: 2011-09-08, release date: 2012-06-20, Last modification date: 2023-12-06)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.8 Å)