ArticlePLoS computational biology2015
Elucidation of Ligand-Dependent Modulation of Disorder-Order Transitions in the Oncoprotein MDM2.
Article in PLoS computational biology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed.
- Molecular driving force of a small molecule-induced protein disorder-order transition.Communications chemistry · 2026Article
- Mechanistic Role of the Mdm2/MdmX Lid Domain in Regulating Their Interactions with p53.Biomolecules · 2025Review
- Computational approaches for the design of modulators targeting protein-protein interactions.Expert opinion on drug discovery · 2023Review
- Ubiquitin receptors play redundant roles in the proteasomal degradation of the p53 repressor MDM2.FEBS letters · 2022Article
- Energetics of a protein disorder-order transition in small molecule recognition.Chemical science · 2022Article
- Resistance mechanisms to inhibitors of p53-MDM2 interactions in cancer therapy: can we overcome them?Cellular & molecular biology letters · 2021Review
- Computational Modeling as a Tool to Investigate PPI: From Drug Design to Tissue Engineering.Frontiers in molecular biosciences · 2021Review
- Computational Investigation on the p53-MDM2 Interaction Using the Potential of Mean Force Study.ACS omega · 2020Article
- Mechanism of allosteric activation of human mRNA cap methyltransferase (RNMT) by RAM: insights from accelerated molecular dynamics simulations.Nucleic acids research · 2019Article
- Roles of computational modelling in understanding p53 structure, biology, and its therapeutic targeting.Journal of molecular cell biology · 2019Review
- Role of the N-terminal lid in regulating the interaction of phosphorylated MDMX with p53.Oncotarget · 2017Article
- Characterizing the conformational landscape of MDM2-binding p53 peptides using Molecular Dynamics simulations.Scientific reports · 2017Article
- Predictions of Backbone Dynamics in Intrinsically Disordered Proteins Using De Novo Fragment-Based Protein Structure Predictions.Scientific reports · 2017Article
- Markov models of the apo-MDM2 lid region reveal diffuse yet two-state binding dynamics and receptor poses for computational docking.Scientific reports · 2016Article
- DIRECT-ID: An automated method to identify and quantify conformational variations--application to β2 -adrenergic GPCR.Journal of computational chemistry · 2016Article
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Authors and funding
2 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Numerous biomolecular interactions involve unstructured protein regions, but how to exploit such interactions to enhance the affinity of a lead molecule in the context of rational drug design remains uncertain. Here clarification was sought for cases where interactions of different ligands with the same disordered protein region yield qualitatively different results. Specifically, conformational ensembles for the disordered lid region of the N-terminal domain of the oncoprotein MDM2 in the presence of different ligands were computed by means of a novel combination of accelerated molecular dynamics, umbrella sampling, and variational free energy profile methodologies. The resulting conformational ensembles for MDM2, free and bound to p53 TAD (17-29) peptide identify lid states compatible with previous NMR measurements. Remarkably, the MDM2 lid region is shown to adopt distinct conformational states in the presence of different small-molecule ligands. Detailed analyses of small-molecule bound ensembles reveal that the ca. 25-fold affinity improvement of the piperidinone family of inhibitors for MDM2 constructs that include the full lid correlates with interactions between ligand hydrophobic groups and the C-terminal lid region that is already partially ordered in apo MDM2. By contrast, Nutlin or benzodiazepinedione inhibitors, that bind with similar affinity to full lid and lid-truncated MDM2 constructs, interact additionally through their solubilizing groups with N-terminal lid residues that are more disordered in apo MDM2.
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