5VK0

Crystal structure of human MDM2 in complex with a 12-mer lysine-cysteine side chain dithiocarbamate stapled peptide inhibitor PMI

Summary for 5VK0

• Entry DOI: 10.2210/pdb5vk0/pdb
• Related: 3EQS 5VK1
• Descriptor: E3 ubiquitin-protein ligase Mdm2, Lysine-cysteine side chain dithiocarbamate stapled peptide inhibitor PMI, CHLORIDE ION, ... (4 entities in total)
• Functional Keywords: mdm2-peptide inhibitor complex, oncoprotein, host-virus interaction, ligase, metal-binding, nucleus, phosphoprotein, proto-oncogene, ubl conjugation pathway, zinc-finger, stapled peptide, ligase-ligase inhibitor complex, ligase/ligase inhibitor
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 24
• Total formula weight: 138823.07

Authors

Tolbert, W.D.,Gohain, N.,Pazgier, M. (deposition date: 2017-04-20, release date: 2018-04-25, Last modification date: 2024-07-10)

Primary citation

Li, X.,Tolbert, W.D.,Hu, H.G.,Gohain, N.,Zou, Y.,Niu, F.,He, W.X.,Yuan, W.,Su, J.C.,Pazgier, M.,Lu, W.
Dithiocarbamate-inspired side chain stapling chemistry for peptide drug design.
Chem Sci, 10:1522-1530, 2019

PubMed Abstract: 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 α-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() and Cys( + 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 (, + 4) positions. One dithiocarbamate-stapled PMI derivative, 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 PMI peptide actively traversed the cell membrane and killed HCT116 tumor cells 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.

PubMed: 30809370
DOI: 10.1039/c8sc03275k

Experimental method

X-RAY DIFFRACTION (1.8 Å)