7NUS

X-RAY STRUCTURE OF HDM2/CMR19 AT 1.45A: Discovery, X-ray structure and CPP-conjugation enabled uptake of p53/MDM2 macrocyclic peptide inhibitors

Summary for 7NUS

• Entry DOI: 10.2210/pdb7nus/pdb
• Descriptor: E3 ubiquitin-protein ligase Mdm2, p53/MDM2 macrocyclic peptide inhibitor, SULFATE ION, ... (5 entities in total)
• Functional Keywords: peptidream, peptide macrocycle, ligase, ppi inhibitor
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 6
• Total formula weight: 39395.32

Authors

Kallen, J. (deposition date: 2021-03-13, release date: 2021-09-22, Last modification date: 2024-01-31)

Primary citation

Schneider, A.F.L.,Kallen, J.,Ottl, J.,Reid, P.C.,Ripoche, S.,Ruetz, S.,Stachyra, T.M.,Hintermann, S.,Dumelin, C.E.,Hackenberger, C.P.R.,Marzinzik, A.L.
Discovery, X-ray structure and CPP-conjugation enabled uptake of p53/MDM2 macrocyclic peptide inhibitors.
Rsc Chem Biol, 2:1661-1668, 2021

PubMed Abstract: Mouse double minute 2 homolog (MDM2, Hdm2) is an important negative regulator of the tumor suppressor p53. Using a mRNA based display technique to screen a library of >10 -translated cyclic peptides, we have identified a macrocyclic ligand that shows picomolar potency on MDM2. X-Ray crystallography reveals a novel binding mode utilizing a unique pharmacophore to occupy the Phe/Trp/Leu pockets on MDM2. Conjugation of a cyclic cell-penetrating peptide (cCPP) to the initially non cell-permeable ligand enables cellular uptake and a pharmacodynamic response in SJSA-1 cells. The demonstrated enhanced intracellular availability of cyclic peptides that are identified by a display technology exemplifies a process for the application of intracellular tools for drug discovery projects.

PubMed: 34977581
DOI: 10.1039/d1cb00056j

Experimental method

X-RAY DIFFRACTION (1.45 Å)