7KJM
CRYSTAL STRUCTURE OF HUMAN MDM2 IN COMPLEX WITH D-PEPTIDE INHIBITOR (DPMI-OMEGA)
Summary for 7KJM
| Entry DOI | 10.2210/pdb7kjm/pdb |
| Related PRD ID | PRD_002455 |
| Descriptor | E3 ubiquitin-protein ligase Mdm2, D-PMI-omega, DI(HYDROXYETHYL)ETHER, ... (6 entities in total) |
| Functional Keywords | mdm2, p53 binding domain, d-peptide activator of mdm2, mdm2-d-peptide complex, host-virus interaction, ligase, metal-binding, nucleus, phosphoprotein, proto-oncogene, ubl conjugation pathway, zinc-finger, ligase-ligase inhibitor complex, ligase/ligase inhibitor |
| Biological source | Homo sapiens (Human) More |
| Total number of polymer chains | 4 |
| Total formula weight | 23715.59 |
| Authors | Tolbert, W.D.,Pazgier, M. (deposition date: 2020-10-26, release date: 2021-11-17, Last modification date: 2025-08-27) |
| Primary citation | Liao, C.,Yan, J.,Tolbert, W.D.,Chen, X.,Pazgier, M.,Lu, W.,Zhan, C.,Lu, W. A Dual-Specificity d-Peptide Antagonist of MDM2 and MDMX for Antitumor Immunotherapy. J.Med.Chem., 2025 Cited by PubMed Abstract: Designing metabolically stable peptides to target interactions of the tumor suppressor protein p53 with the two oncogenic proteins MDM2 and MDMX represents an attractive approach to harvesting "high-hanging fruits" often inaccessible to traditional anticancer drug discovery and development efforts. Here, we report the design of a proteolysis-resistant d-dodecapeptide, termed PMI-ω (EFWYVEFEKLLR), capable of disrupting the p53-MDM2/MDMX complex by antagonizing MDM2 and MDMX. PMI-ω, upon fabrication on gold nanoparticles, efficiently traversed tumor cells and killed them by reactivating the p53 signaling pathway. Further, PMI-ω inhibited B16 melanoma growth and, when combined with an anti-PD1 antibody, powerfully augmented the efficacy of immunotherapy by expanding CD3/CD8 cytotoxic T cells and suppressing CD4/CD25 regulatory T cells. Our work validates the design of a therapeutically viable anticancer peptide, showcasing its potential in combination therapy to treat patients with tumors that are otherwise resistant or poorly responsive to antitumor immunotherapy. PubMed: 40824889DOI: 10.1021/acs.jmedchem.4c02057 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.4 Å) |
Structure validation
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