8AEU

Structure of hMDM2 in complex with Nutlin-3a-aa

Summary for 8AEU

• Entry DOI: 10.2210/pdb8aeu/pdb
• Descriptor: E3 ubiquitin-protein ligase Mdm2, BETA-MERCAPTOETHANOL, 4-[[(4~{S},5~{R})-4,5-bis(4-chlorophenyl)-2-(4-methoxy-2-propan-2-yloxy-phenyl)-4,5-dihydroimidazol-1-yl]carbonyl]-3-methylidene-piperazin-2-one, ... (4 entities in total)
• Functional Keywords: biological activity, drug design, inhibitors, protein-protein interactions, ligase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 12071.01

Authors

Labuzek, B.,Golik, P.,Magiera-Mularz, K.,Berg, T. (deposition date: 2022-07-13, release date: 2023-01-18, Last modification date: 2024-02-07)

Primary citation

Nietzold, F.,Rubner, S.,Labuzek, B.,Golik, P.,Surmiak, E.,Del Corte, X.,Kitel, R.,Protzel, C.,Reppich-Sacher, R.,Stichel, J.,Magiera-Mularz, K.,Holak, T.A.,Berg, T.
Nutlin-3a-aa: Improving the Bioactivity of a p53/MDM2 Interaction Inhibitor by Introducing a Solvent-Exposed Methylene Group.
Chembiochem, 24:e202300006-e202300006, 2023

PubMed Abstract: Nutlin-3a is a reversible inhibitor of the p53/MDM2 interaction. We have synthesized the derivative Nutlin-3a-aa bearing an additional exocyclic methylene group in the piperazinone moiety. Nutlin-3a-aa is more active than Nutlin-3a against purified wild-type MDM2, and is more effective at increasing p53 levels and releasing transcription of p53 target genes from MDM2-induced repression. X-ray analysis of wild-type MDM2-bound Nutlin-3a-aa indicated that the orientation of its modified piperazinone ring was altered in comparison to the piperazinone ring of MDM2-bound Nutlin-3a, with the exocyclic methylene group of Nutlin-3a-aa pointing away from the protein surface. Our data point to the introduction of exocyclic methylene groups as a useful approach by which to tailor the conformation of bioactive molecules for improved biological activity.

PubMed: 36602436
DOI: 10.1002/cbic.202300006

Experimental method

X-RAY DIFFRACTION (2 Å)