3EQS

Crystal structure of human MDM2 in complex with a 12-mer peptide inhibitor

Summary for 3EQS

• Entry DOI: 10.2210/pdb3eqs/pdb
• Related: 1RV1 1T4E 1T4F 1YCR
• Descriptor: E3 ubiquitin-protein ligase Mdm2, 12-mer peptide inhibitor, GUANIDINE, ... (4 entities in total)
• Functional Keywords: mdm2, mdm2-peptide inhibitor complex, oncoprotein, host-virus interaction, ligase, metal-binding, nucleus, phosphoprotein, proto-oncogene, ubl conjugation pathway, zinc-finger
• Cellular location: Nucleus, nucleoplasm: Q00987
• Total number of polymer chains: 2
• Total formula weight: 11531.52

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 (1.65 Å)