ArticlePloS one2014
Structure of a stapled peptide antagonist bound to nutlin-resistant Mdm2.
Article in PloS one, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 39 citations in OpenAlex.
- Dichotomous transactivation domains contribute to growth inhibitory and promotion functions of TAp73.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Functional display of bioactive peptides on the vGFP scaffold.Scientific reports · 2021Article
- Peptide-based inhibitors of protein-protein interactions: biophysical, structural and cellular consequences of introducing a constraint.Chemical science · 2021Review
- Enhancing the therapeutic effects of in vitro targeted radionuclide therapy of 3D multicellular tumor spheroids using the novel stapled MDM2/X-p53 antagonist PM2.EJNMMI research · 2020Article
- Rigorous Computational and Experimental Investigations on MDM2/MDMX-Targeted Linear and Macrocyclic Peptides.Molecules (Basel, Switzerland) · 2019Article
- Development and structural characterization of an engineered multi-copper oxidase reporter of protein-protein interactions.The Journal of biological chemistry · 2019Article
- Stapled Peptides Inhibitors: A New Window for Target Drug Discovery.Computational and structural biotechnology journal · 2019Review
- Artificial Macrocycles as Potent p53-MDM2 Inhibitors.ACS medicinal chemistry letters · 2017Article
- Structure-activity studies of Mdm2/Mdm4-binding stapled peptides comprising non-natural amino acids.PloS one · 2017Article
- Functional characterization of p53 pathway components in the ancient metazoan Trichoplax adhaerens.Scientific reports · 2016Article
- Benzene Probes in Molecular Dynamics Simulations Reveal Novel Binding Sites for Ligand Design.The journal of physical chemistry letters · 2016Article
- Avoiding drug resistance through extended drug target interfaces: a case for stapled peptides.Oncotarget · 2016Article
- The Roles of MDM2 and MDMX in Cancer.Annual review of pathology · 2016Review
- How To Design a Successful p53-MDM2/X Interaction Inhibitor: A Thorough Overview Based on Crystal Structures.ChemMedChem · 2016Review
- The p53-Mdm2 interaction and the E3 ligase activity of Mdm2/Mdm4 are conserved from lampreys to humans.Genes & development · 2016Article
- Energetic Landscape of MDM2-p53 Interactions by Computational Mutagenesis of the MDM2-p53 Interaction.PloS one · 2016Article
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
As key negative regulator of the p53 tumour suppressor, Mdm2 is an attractive therapeutic target. Small molecules such as Nutlin have been developed to antagonise Mdm2, resulting in p53-dependent death of tumour cells. We have recently described a mutation in Mdm2 (M62A), which precludes binding of Nutlin, but not p53. This Nutlin-resistant variant is not, however, refractory to binding and inhibition by stapled peptide antagonists targeting the same region of Mdm2. A detailed understanding of how stapled peptides are recalcitrant to Mdm2 mutations conferring Nutlin-resistance will aid in the further development of potent Mdm2 antagonists. Here, we report the 2.00 Å crystal structure of a stapled peptide antagonist bound to Nutlin resistant Mdm2. The stapled peptide relies on an extended network of interactions along the hydrophobic binding cleft of Mdm2 for high affinity binding. Additionally, as seen in other stapled peptide structures, the hydrocarbon staple itself contributes to binding through favourable interactions with Mdm2. The structure highlights the intrinsic plasticity present in both Mdm2 and the hydrocarbon staple moiety, and can be used to guide future iterations of both small molecules and stapled peptides for improved antagonists of Mdm2.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.