ArticleNature chemistry2018
Towards simple kinetic models of functional dynamics for a kinase subfamily.
Article in Nature chemistry, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 76 citations in OpenAlex.
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- Independent Markov decomposition: Toward modeling kinetics of biomolecular complexes.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Reduced efficacy of a Src kinase inhibitor in crowded protein solution.Nature communications · 2021Article
- Untangling Dual-Targeting Therapeutic Mechanism of Epidermal Growth Factor Receptor (EGFR) Based on Reversed Allosteric Communication.Pharmaceutics · 2021Article
- Discovery of a hidden transient state in all bromodomain families.Proceedings of the National Academy of Sciences of the United States of America · 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
- Discovery of cryptic allosteric sites using reversed allosteric communication by a combined computational and experimental strategy.Chemical science · 2020Article
- Caffeoyl-Prolyl-Histidine Amide Inhibits Fyn and Alleviates Atopic Dermatitis-Like Phenotypes via Suppression of NF-κB Activation.International journal of molecular sciences · 2020Article
- Activation Loop Dynamics Are Coupled to Core Motions in Extracellular Signal-Regulated Kinase-2.Biochemistry · 2020Article
Corrections and comments
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Authors and funding
3 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Kinases are ubiquitous enzymes involved in the regulation of critical cellular pathways. However, in silico modelling of the conformational ensembles of these enzymes is difficult due to inherent limitations and the cost of computational approaches. Recent algorithmic advances combined with homology modelling and parallel simulations have enabled researchers to address this computational sampling bottleneck. Here, we present the results of molecular dynamics studies for seven Src family kinase (SFK) members: Fyn, Lyn, Lck, Hck, Fgr, Yes and Blk. We present a sequence invariant extension to Markov state models, which allows us to quantitatively compare the structural ensembles of the seven kinases. Our findings indicate that in the absence of their regulatory partners, SFK members have similar in silico dynamics with active state populations ranging from 4 to 40% and activation timescales in the hundreds of microseconds. Furthermore, we observe several potentially druggable intermediate states, including a pocket next to the adenosine triphosphate binding site that could potentially be targeted via a small-molecule inhibitor.
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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.