ArticleJournal of the American Chemical Society2019
How Electrostatic Coupling Enables Conformational Plasticity in a Tyrosine Kinase.
Article in Journal of the American Chemical Society, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
23 citing papers in PubMed.
- QM/MM Free Energy Calculations of IRE1 Reveal a Unique Protonation State of the Catalytic Lys599.Journal of computational chemistry · 2025Article
- Article
- The role of ribosomal protein networks in ribosome dynamics.Nucleic acids research · 2025Article
- Multistate Method to Efficiently Account for Tautomerism and Protonation in Alchemical Free-Energy Calculations.Journal of chemical theory and computation · 2024Article
- Classifying protein kinase conformations with machine learning.Protein science : a publication of the Protein Society · 2024Article
- Perspectives on Computational Enzyme Modeling: From Mechanisms to Design and Drug Development.ACS omega · 2024Review
- Deciphering the molecular choreography of Janus kinase 2 inhibition via Gaussian accelerated molecular dynamics simulations: a dynamic odyssey.Journal of computer-aided molecular design · 2024Article
- The role of kinases in peripheral nerve regeneration: mechanisms and implications.Frontiers in neurology · 2024Review
- Molecular Simulations of Conformational Transitions within the Insulin Receptor Kinase Reveal Consensus Features in a Multistep Activation Pathway.The journal of physical chemistry. B · 2023Article
- Mechanistic Modeling of Lys745 Sulfonylation in EGFR C797S Reveals Chemical Determinants for Inhibitor Activity and Discriminates Reversible from Irreversible Agents.Journal of chemical information and modeling · 2023Article
- Constant pH molecular dynamics simulations: Current status and recent applications.Current opinion in structural biology · 2022Review
- Mechanical force can enhance c-Src kinase activity by impairing autoinhibition.Biophysical journal · 2022Article
- Reactivities of the Front Pocket N-Terminal Cap Cysteines in Human Kinases.Journal of medicinal chemistry · 2022Article
- Profiling MAP kinase cysteines for targeted covalent inhibitor design.RSC medicinal chemistry · 2022Article
- A Guide to the Continuous Constant pH Molecular Dynamics Methods in Amber and CHARMM [Article v1.0].Living journal of computational molecular science · 2022Article
- Activation of Abl1 Kinase Explored Using Well-Tempered Metadynamics Simulations on an Essential Dynamics Sampled Path.Journal of chemical theory and computation · 2021Article
- Reduced efficacy of a Src kinase inhibitor in crowded protein solution.Nature communications · 2021Article
- Atomistic dynamics of a viral infection process: Release of membrane lytic peptides from a non-enveloped virus.Science advances · 2021Article
- Article
- Continuous Constant pH Molecular Dynamics Simulations of Transmembrane Proteins.Methods in molecular biology (Clifton, N.J.) · 2021Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
3 authors.
Funding
Abstract
Protein kinases are important cellular signaling molecules involved in cancer and a multitude of other diseases. It is well-known that inactive kinases display a remarkable conformational plasticity; however, the molecular mechanisms remain poorly understood. Conformational heterogeneity presents an opportunity but also a challenge in kinase drug discovery. The ability to predictively model various conformational states could accelerate selective inhibitor design. Here we performed a proton-coupled molecular dynamics study to explore the conformational landscape of a c-Src kinase. Starting from a completely inactive structure, the simulations captured all major types of conformational states without the use of a target structure, mutation, or bias. The simulations allowed us to test the experimental hypotheses regarding the mechanism of DFG flip, its coupling to the αC-helix movement, and the formation of regulatory spine. Perhaps the most significant finding is how key titratable residues, such as DFG-Asp, αC-Glu, and HRD-Asp, change protonation states dependent on the DFG, αC, and activation loop conformations. Our data offer direct evidence to support a long-standing hypothesis that protonation of Asp favors the DFG-out state and explain why DFG flip is also possible in simulations with deprotonated Asp. The simulations also revealed intermediate states, among which a unique DFG-out/α-C state formed as DFG-Asp is moved into a back pocket forming a salt bridge with catalytic Lys, which can be tested in selective inhibitor design. Our finding of how proton coupling enables the remarkable conformational plasticity may shift the paradigm of computational studies of kinases which assume fixed protonation states. Understanding proton-coupled conformational dynamics may hold a key to further innovation in kinase drug discovery.
Indexed as
Identifiers
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.