9gfk

human MDM2 complex with stapled foldamer

spinqualitylabelsall models 9gfk, resolution 1.84Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9gfk is a 8 chain structure with sequence from Homo sapiens and Synthetic construct. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.841Å Ligands: A1IL6, NH2, SO4, URL Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease MDM2_HUMAN Note=Seems to be amplified in certain tumors (including soft tissue sarcomas, osteosarcomas and gliomas). A higher frequency of splice variants lacking p53 binding domain sequences was found in late-stage and high-grade ovarian and bladder carcinomas. Four of the splice variants show loss of p53 binding. Function MDM2_HUMAN E3 ubiquitin-protein ligase that mediates ubiquitination of p53/TP53, leading to its degradation by the proteasome. Inhibits p53/TP53- and p73/TP73-mediated cell cycle arrest and apoptosis by binding its transcriptional activation domain. Also acts as an ubiquitin ligase E3 toward itself and ARRB1. Permits the nuclear export of p53/TP53. Promotes proteasome-dependent ubiquitin-independent degradation of retinoblastoma RB1 protein. Inhibits DAXX-mediated apoptosis by inducing its ubiquitination and degradation. Component of the TRIM28/KAP1-MDM2-p53/TP53 complex involved in stabilizing p53/TP53. Also component of the TRIM28/KAP1-ERBB4-MDM2 complex which links growth factor and DNA damage response pathways. Mediates ubiquitination and subsequent proteasome degradation of DYRK2 in nucleus. Ubiquitinates IGF1R and promotes it to proteasomal degradation. Publication Abstract from PubMed Structural analysis of a co-crystal of a helically-folded peptide-foldamer hybrid in complex with hDM2 E3 ubiquitin ligase, revealed a unique orientation for the C-terminal proline with the pyrrolidine ring pointing backwards in the sequence, and suggested new opportunities for macrocyclization. In particular, we found that the C-terminal prolyl residue could be replaced by its (2S,4S)-4-mercaptoprolyl analogue for optimal bisthioether crosslinking with a cysteine residue installed at position 4 in the sequence. The resulting i,i+7 stapled peptide-foldamer is a high-affinity binder to hDM2, is cell permeable and restores the p53 signalling pathway in p53wt cancer cells. The co-crystal structure of hDM2 and the stapled peptide-foldamer hybrid was determined at 1.84 A, fully validating the original design and further highlighting the potential of cis-4-mercaptoproline in the context of peptide and foldamer stapling. Optimal Stapling of a Helical Peptide-Foldamer Hybrid Using a C-Terminal 4-Mercaptoproline Enhances Protein Surface Recognition and Cellular Activity.,Neuville M, Bourgeais M, Buratto J, Saragaglia C, Li B, Galeano-Otero I, Mauran L, Varajao L, Goudreau SR, Kauffmann B, Thinon E, Pasco M, Khatib AM, Guichard G Chemistry. 2025 Feb 27:e202403330. doi: 10.1002/chem.202403330. PMID:40014761 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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