6t2e

Multicomponent Peptide Stapling as a Diversity-Driven Tool for the Development of Inhibitors of Protein-Protein InteractionsMulticomponent Peptide Stapling as a Diversity-Driven Tool for the Development of Inhibitors of Protein-Protein Interactions

Structural highlights 6t2e is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Activity: RING-type E3 ubiquitin transferase, with EC number 2.3.2.27 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 Stapled peptides are chemical entities in-between biologics and small molecules, which have proven to be the solution to high affinity protein-protein interaction antagonism while keeping control over pharmacological performance such as stability and membrane penetration. We demonstrate that the multicomponent reaction-based stapling is an effective strategy for the development of alpha-helical peptides with highly potent dual antagonistic action of MDM2 and MDMX binding p53. Such a potent inhibitory activity of p53-MDM2/X interactions was assessed by fluorescence polarization, microscale thermophoresis and 2D NMR, while several cocrystal structures with MDM2 were obtained. This MCR stapling protocol proved efficient and versatile in terms of diversity generation at the staple, as evidenced by the incorporation of both exo - and endo -cyclic hydrophobic moieties at the side chain cross-linkers. The interaction of the Ugi-staple fragments with the target protein was demonstrated by crystallography, while the difference in ring sizes, flexibility and number of amide bonds within the ring seem to be crucial for a potent activity. Multicomponent Peptide Stapling as a Diversity-Driven Tool for the Development of Inhibitors of Protein-Protein Interactions.,Doemling A, Ricardo M, Ali A, Plewka J, Surmiak E, Labuzek B, Neochoritis C, Atmaj J, Skalniak L, Zhang R, Holak T, Groves M, Rivera D Angew Chem Int Ed Engl. 2020 Jan 15. doi: 10.1002/anie.201916257. PMID:31944488 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

spinqualitylabelsall models 6t2e, resolution 2.40Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image