5vk1

Crystal structure of human MDM4 in complex with a 12-mer lysine-cysteine side chain dithiocarbamate stapled peptide inhibitor PMI

spinqualitylabelsall models 5vk1, resolution 2.69Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5vk1 is a 16 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 2.69Å Ligands: 9E7, ACE, NH2 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function MDM4_HUMAN Inhibits p53/TP53- and TP73/p73-mediated cell cycle arrest and apoptosis by binding its transcriptional activation domain. Inhibits degradation of MDM2. Can reverse MDM2-targeted degradation of TP53 while maintaining suppression of TP53 transactivation and apoptotic functions. Publication Abstract from PubMed Two major pharmacological hurdles severely limit the widespread use of small peptides as therapeutics: poor proteolytic stability and membrane permeability. Importantly, low aqueous solubility also impedes the development of peptides for clinical use. Various elaborate side chain stapling chemistries have been developed for alpha-helical peptides to circumvent this problem, with considerable success in spite of inevitable limitations. Here we report a novel peptide stapling strategy based on the dithiocarbamate chemistry linking the side chains of residues Lys(i) and Cys(i + 4) of unprotected peptides and apply it to a series of dodecameric peptide antagonists of the p53-inhibitory oncogenic proteins MDM2 and MDMX. Crystallographic studies of peptide-MDM2/MDMX complexes structurally validated the chemoselectivity of the dithiocarbamate staple bridging Lys and Cys at (i, i + 4) positions. One dithiocarbamate-stapled PMI derivative, (DTC)PMI, showed a 50-fold stronger binding to MDM2 and MDMX than its linear counterpart. Importantly, in contrast to PMI and its linear derivatives, the (DTC)PMI peptide actively traversed the cell membrane and killed HCT116 tumor cells in vitro by activating the tumor suppressor protein p53. Compared with other known stapling techniques, our solution-based DTC stapling chemistry is simple, cost-effective, regio-specific and environmentally friendly, promising an important new tool for the development of peptide therapeutics with improved pharmacological properties including aqueous solubility, proteolytic stability and membrane permeability. Dithiocarbamate-inspired side chain stapling chemistry for peptide drug design.,Li X, Tolbert WD, Hu HG, Gohain N, Zou Y, Niu F, He WX, Yuan W, Su JC, Pazgier M, Lu W Chem Sci. 2018 Nov 30;10(5):1522-1530. doi: 10.1039/c8sc03275k. eCollection 2019 , Feb 7. PMID:30809370 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also MDM4

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