ArticleScientific reports2017
Millisecond dynamics of BTK reveal kinome-wide conformational plasticity within the apo kinase domain.
Article in Scientific reports, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 50 citations in OpenAlex.
- Pan-Cancer Landscape and Analysis of ERBB2 Mutations Identifies Poziotinib as a Clinically Active Inhibitor and Enhancer of T-DM1 Activity.Cancer cell · 2019Trial
- Large-scale comparative virtual screening identifies novel molecular targets underlying the multi-target activity of quercetin in psoriasis.Inflammopharmacology · 2026Article
- Bruton's Tyrosine Kinase Inhibitors in Multiple Sclerosis: Mechanistic Considerations Across Relapsing and Progressive Disease.Molecules (Basel, Switzerland) · 2026Review
- Exploring pocket-aware inhibitors of BTK kinase by generative deep learning, molecular docking, and molecular dynamics simulations.RSC advances · 2025Article
- A comprehensive exploration of the druggable conformational space of protein kinases using AI-predicted structures.PLoS computational biology · 2024Article
- Discovery of new symmetrical and asymmetrical nitrile-containing 1,4-dihydropyridine derivatives as dual kinases and P-glycoprotein inhibitors: synthesis,Journal of enzyme inhibition and medicinal chemistry · 2022Article
- Comparison of Intermolecular Interactions of Irreversible and Reversible Inhibitors with Bruton's Tyrosine Kinase via Molecular Dynamics Simulations.Molecules (Basel, Switzerland) · 2022Article
- Insights on Aggregation of Hen Egg-White Lysozyme from Raman Spectroscopy and MD Simulations.Molecules (Basel, Switzerland) · 2022Article
- Pre-exascale HPC approaches for molecular dynamics simulations. Covid-19 research: A use case.Wiley interdisciplinary reviews. Computational molecular science · 2022Article
- A mechanism for localized dynamics-driven activation in Bruton's tyrosine kinase.Royal Society open science · 2021Article
- Article
- Protein Loop Conformational Free Energy Changes via an Alchemical Path without Reaction Coordinates.The journal of physical chemistry letters · 2021Article
- What Markov State Models Can and Cannot Do: Correlation versus Path-Based Observables in Protein-Folding Models.Journal of chemical theory and computation · 2021Article
- Specific PIPCommunications biology · 2021Article
- All-atom adaptively biased path optimization of Src kinase conformational inactivation: Switched electrostatic network in the concerted motion of αC helix and the activation loop.The Journal of chemical physics · 2020Article
- Structural and biophysical insights into the mode of covalent binding of rationally designed potent BMX inhibitors.RSC chemical biology · 2020Article
- Dynamics, a Powerful Component of Current and Future in Silico Approaches for Protein Design and Engineering.International journal of molecular sciences · 2020Review
- A Dynamic Switch in Inactive p38γ Leads to an Excited State on the Pathway to an Active Kinase.Biochemistry · 2019Article
- Structural Characterization of the Aurora Kinase B "DFG-flip" Using Metadynamics.The AAPS journal · 2019Article
- Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Bruton tyrosine kinase (BTK) is a key enzyme in B-cell development whose improper regulation causes severe immunodeficiency diseases. Design of selective BTK therapeutics would benefit from improved, in-silico structural modeling of the kinase's solution ensemble. However, this remains challenging due to the immense computational cost of sampling events on biological timescales. In this work, we combine multi-millisecond molecular dynamics (MD) simulations with Markov state models (MSMs) to report on the thermodynamics, kinetics, and accessible states of BTK's kinase domain. Our conformational landscape links the active state to several inactive states, connected via a structurally diverse intermediate. Our calculations predict a kinome-wide conformational plasticity, and indicate the presence of several new potentially druggable BTK states. We further find that the population of these states and the kinetics of their inter-conversion are modulated by protonation of an aspartate residue, establishing the power of MD & MSMs in predicting effects of chemical perturbations.
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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.