ArticlePloS one2017
Structure-activity studies of Mdm2/Mdm4-binding stapled peptides comprising non-natural amino acids.
Article in PloS one, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
What it found
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Who cites it
8 citing papers in PubMed, 10 citations in OpenAlex.
- The MDM2 Inhibitor Navtemadlin Arrests Mouse Melanoma GrowthCancer research communications · 2022Article
- Design and synthesis of Nrf2-derived hydrocarbon stapled peptides for the disruption of protein-DNA-interactions.PloS one · 2022Article
- Functional display of bioactive peptides on the vGFP scaffold.Scientific reports · 2021Article
- Investigation of the Role of Aromatic Residues in the Antimicrobial Peptide BuCATHL4B.Protein and peptide letters · 2021Article
- miR‑205 suppresses cell migration, invasion and EMT of colon cancer by targeting mouse double minute 4.Molecular medicine reports · 2020Article
- Small molecule activators of the p53 response.Journal of molecular cell biology · 2019Review
- The long and the short of it: the MDM4 tail so far.Journal of molecular cell biology · 2019Review
- Stapled Peptides Inhibitors: A New Window for Target Drug Discovery.Computational and structural biotechnology journal · 2019Review
Corrections and comments
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Authors and funding
9 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
As primary p53 antagonists, Mdm2 and the closely related Mdm4 are relevant cancer therapeutic targets. We have previously described a series of cell-permeable stapled peptides that bind to Mdm2 with high affinity, resulting in activation of the p53 tumour suppressor. Within this series, highest affinity was obtained by modification of an obligate tryptophan residue to the non-natural L-6-chlorotryptophan. To understand the structural basis for improved affinity we have solved the crystal structure of this stapled peptide (M011) bound to Mdm2 (residues 6-125) at 1.66 Å resolution. Surprisingly, near identity to the structure of a related peptide (M06) without the 6-chloro modification is observed. Further analysis of linear and stapled peptides comprising 6-Me-tryptophan provides mechanistic insight into dual Mdm2/Mdm4 antagonism and confirms L98 of Mdm4 as a mutable steric gate. The results also highlight a possible role of the flexible hinge region in determining Mdm2/Mdm4 plasticity.
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Registered trials
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.