3IWY

Crystal structure of human MDM2 complexed with D-peptide (12 residues)

Summary for 3IWY

• Entry DOI: 10.2210/pdb3iwy/pdb
• Related: 1YCR 3EQS 3IUX
• Related PRD ID: PRD_001088
• Descriptor: D-peptide inhibitor, E3 ubiquitin-protein ligase Mdm2 (3 entities in total)
• Functional Keywords: mdm2, p53 binding domain, d-peptide activator of p53, host-virus interaction, ligase, metal-binding, nucleus, phosphoprotein, proto-oncogene, ubl conjugation pathway, zinc-finger, ligase-ligase inhibitor complex, ligase/ligase inhibitor
• Cellular location: Nucleus, nucleoplasm: Q00987
• Total number of polymer chains: 4
• Total formula weight: 23125.27

Authors

Pazgier, M.,Lu, W. (deposition date: 2009-09-03, release date: 2010-04-21, Last modification date: 2024-11-20)

Primary citation

Liu, M.,Li, C.,Pazgier, M.,Li, C.,Mao, Y.,Lv, Y.,Gu, B.,Wei, G.,Yuan, W.,Zhan, C.,Lu, W.Y.,Lu, W.
D-peptide inhibitors of the p53-MDM2 interaction for targeted molecular therapy of malignant neoplasms.
Proc.Natl.Acad.Sci.USA, 398:200-213, 2010

PubMed Abstract: The oncoproteins MDM2 and MDMX negatively regulate the activity and stability of the tumor suppressor protein p53, conferring tumor development and survival. Antagonists targeting the p53-binding domains of MDM2 and MDMX kill tumor cells both in vitro and in vivo by reactivating the p53 pathway, promising a class of antitumor agents for cancer therapy. Aided by native chemical ligation and mirror image phage display, we recently identified a D-peptide inhibitor of the p53-MDM2 interaction termed (D)PMI-alpha (TNWYANLEKLLR) that competes with p53 for MDM2 binding at an affinity of 219 nM. Increased selection stringency resulted in a distinct D-peptide inhibitor termed (D)PMI-gamma (DWWPLAFEALLR) that binds MDM2 at an affinity of 53 nM. Structural studies coupled with mutational analysis verified the mode of action of these D-peptides as MDM2-dependent p53 activators. Despite being resistant to proteolysis, both (D)PMI-alpha and (D)PMI-gamma failed to actively traverse the cell membrane and, when conjugated to a cationic cell-penetrating peptide, were indiscriminately cytotoxic independently of p53 status. When encapsulated in liposomes decorated with an integrin-targeting cyclic-RGD peptide, however, (D)PMI-alpha exerted potent p53-dependent growth inhibitory activity against human glioblastoma in cell cultures and nude mouse xenograft models. Our findings validate D-peptide antagonists of MDM2 as a class of p53 activators for targeted molecular therapy of malignant neoplasms harboring WT p53 and elevated levels of MDM2.

PubMed: 20660730
DOI: 10.1073/pnas.1008930107

Experimental method

X-RAY DIFFRACTION (1.93 Å)