9gfk
From Proteopedia
human MDM2 complex with stapled foldamer
Structural highlights
DiseaseMDM2_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. FunctionMDM2_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.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] Publication Abstract from PubMedStructural 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[12] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Homo sapiens | Large Structures | Synthetic construct | Bo L | Bourgeais M | Buratto J | Goudreau SR | Kauffmann B | Khatib AM | Mauran L | Neuville M | Pasco M | Saragaglia C | Thinon E | Varajao L
