ArticleChemical science2020
Markov state models and NMR uncover an overlooked allosteric loop in p53.
Article in Chemical science, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 47 citations in OpenAlex.
- Role of Hsp70 chaperone in client-protein folding elucidated by Markov state modeling and NMR restraint-assisted molecular dynamics simulations.Biophysical journal · 2026Article
- A continuous-space analytical framework for committor functions from molecular dynamics.The Journal of chemical physics · 2026Article
- Restoration of the Y220C p53 Full-Length Mutant by PK11000: a Molecular Dynamics Study of an Intrinsically Disordered Protein.ACS omega · 2026Article
- Understanding the conformational dynamics of PI3Kα due to helical domain mutations: insights from Markov state model analysis.Molecular diversity · 2025Article
- Markovian state models uncover casein kinase 1 dynamics that govern circadian period.Biophysical journal · 2025Article
- TowardsbioRxiv : the preprint server for biology · 2025Article
- Network Theory Analysis of Allosteric Drug-Rescue Mechanisms in the Tumor Suppressor Protein p53 Y220C Mutant.International journal of molecular sciences · 2025Article
- Memory kernel minimization-based neural networks for discovering slow collective variables of biomolecular dynamics.Nature computational science · 2025Article
- AMUSET-TICA: A Tensor-Based Approach for Identifying Slow Collective Variables in Biomolecular Dynamics.Journal of chemical theory and computation · 2025Article
- Dissecting Large-Scale Structural Transitions in Membrane Transporters Using Advanced Simulation Technologies.The journal of physical chemistry. B · 2025Review
- Exploring transition states of protein conformational changes via out-of-distribution detection in the hyperspherical latent space.Nature communications · 2025Article
- Anticancer therapeutic strategies for targeting mutant p53-Y220C.Journal of biomedical research · 2024Article
- Tutorial on how to build non-Markovian dynamic models from molecular dynamics simulations for studying protein conformational changes.The Journal of chemical physics · 2024Article
- Toward physics-based precision medicine: Exploiting protein dynamics to design new therapeutics and interpret variants.Protein science : a publication of the Protein Society · 2024Review
- An Efficient Path Classification Algorithm Based on Variational Autoencoder to Identify Metastable Path Channels for Complex Conformational Changes.Journal of chemical theory and computation · 2023Article
- A Small Molecule Reacts with the p53 Somatic Mutant Y220C to Rescue Wild-type Thermal Stability.Cancer discovery · 2023Article
- Allostery: Allosteric Cancer Drivers and Innovative Allosteric Drugs.Journal of molecular biology · 2022Review
- Structural Basis of Mutation-Dependent p53 Tetramerization Deficiency.International journal of molecular sciences · 2022Article
- Markov State Models to Study the Functional Dynamics of Proteins in the Wake of Machine Learning.JACS Au · 2021Review
- New perspectives in cancer drug development: computational advances with an eye to design.RSC medicinal chemistry · 2021Review
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
The tumor suppressor p53 is the most frequently mutated gene in human cancer, and thus reactivation of mutated p53 is a promising avenue for cancer therapy. Analysis of wildtype p53 and the Y220C cancer mutant long-timescale molecular dynamics simulations with Markov state models and validation by NMR relaxation studies has uncovered the involvement of loop L6 in the slowest motions of the protein. Due to its distant location from the DNA-binding surface, the conformational dynamics of this loop has so far remained largely unexplored. We observe mutation-induced stabilization of alternate L6 conformations, distinct from all experimentally-determined structures, in which the loop is both extended and located further away from the DNA-interacting surface. Additionally, the effect of the L6-adjacent Y220C mutation on the conformational landscape of the functionally-important loop L1 suggests an allosteric role to this dynamic loop and the inactivation mechanism of the mutation. Finally, the simulations reveal a novel Y220C cryptic pocket that can be targeted for p53 rescue efforts. Our approach exemplifies the power of the MSM methodology for uncovering intrinsic dynamic and kinetic differences among distinct protein ensembles, such as for the investigation of mutation effects on protein function.
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What OpenQuestion holds
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.