3EQY

Crystal structure of human MDMX in complex with a 12-mer peptide inhibitor

Summary for 3EQY

• Entry DOI: 10.2210/pdb3eqy/pdb
• Related: 2Z5S 2Z5T 3DAB 3DAC 3EQS
• Descriptor: Mdm4 protein, 12-mer peptide inhibitor, GUANIDINE, ... (5 entities in total)
• Functional Keywords: mdm4, mdmx, mdmx-peptide inhibitor complex, oncoprotein, metal-binding, nucleus, zinc-finger
• Biological source: Homo sapiens (human); More
• Cellular location: Nucleus: O15151
• Total number of polymer chains: 4
• Total formula weight: 22503.72

Authors

Pazgier, M.,Lu, W. (deposition date: 2008-10-01, release date: 2009-03-17, Last modification date: 2023-09-06)

Primary citation

Pazgier, M.,Liu, M.,Zou, G.,Yuan, W.,Li, C.,Li, C.,Li, J.,Monbo, J.,Zella, D.,Tarasov, S.G.,Lu, W.
Structural basis for high-affinity peptide inhibition of p53 interactions with MDM2 and MDMX.
Proc.Natl.Acad.Sci.USA, 106:4665-4670, 2009

PubMed Abstract: The oncoproteins MDM2 and MDMX negatively regulate the activity and stability of the tumor suppressor protein p53--a cellular process initiated by MDM2 and/or MDMX binding to the N-terminal transactivation domain of p53. MDM2 and MDMX in many tumors confer p53 inactivation and tumor survival, and are important molecular targets for anticancer therapy. We screened a duodecimal peptide phage library against site-specifically biotinylated p53-binding domains of human MDM2 and MDMX chemically synthesized via native chemical ligation, and identified several peptide inhibitors of the p53-MDM2/MDMX interactions. The most potent inhibitor (TSFAEYWNLLSP), termed PMI, bound to MDM2 and MDMX at low nanomolar affinities--approximately 2 orders of magnitude stronger than the wild-type p53 peptide of the same length (ETFSDLWKLLPE). We solved the crystal structures of synthetic MDM2 and MDMX, both in complex with PMI, at 1.6 A resolution. Comparative structural analysis identified an extensive, tightened intramolecular H-bonding network in bound PMI that contributed to its conformational stability, thus enhanced binding to the 2 oncogenic proteins. Importantly, the C-terminal residue Pro of PMI induced formation of a hydrophobic cleft in MDMX previously unseen in the structures of p53-bound MDM2 or MDMX. Our findings deciphered the structural basis for high-affinity peptide inhibition of p53 interactions with MDM2 and MDMX, shedding new light on structure-based rational design of different classes of p53 activators for potential therapeutic use.

PubMed: 19255450
DOI: 10.1073/pnas.0900947106

Experimental method

X-RAY DIFFRACTION (1.63 Å)