ArticleJournal of molecular biology2014
A conserved isoleucine maintains the inactive state of Bruton's tyrosine kinase.
Article in Journal of molecular biology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 12 citations in OpenAlex.
- De novo design of tyrosine and serine kinase-driven protein switches.Nature structural & molecular biology · 2021Article
- Genetic cause for congenital methemoglobinemia in an Australian Pomeranian dog.Journal of veterinary internal medicine · 2019Article
- The Src module: an ancient scaffold in the evolution of cytoplasmic tyrosine kinases.Critical reviews in biochemistry and molecular biology · 2018Review
- Subzero Celsius separations in three-zone temperature controlled hydrogen deuterium exchange mass spectrometry.Journal of chromatography. A · 2017Article
- Achieving a Graded Immune Response: BTK Adopts a Range of Active/Inactive Conformations Dictated by Multiple Interdomain Contacts.Structure (London, England : 1993) · 2017Article
- A dynamic hydrophobic core orchestrates allostery in protein kinases.Science advances · 2017Article
- Article
- Dynamic Allostery Mediated by a Conserved Tryptophan in the Tec Family Kinases.PLoS computational biology · 2016Article
- Dynamics-Driven Allostery in Protein Kinases.Trends in biochemical sciences · 2015Review
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
Despite high level of homology among non-receptor tyrosine kinases, different kinase families employ a diverse array of regulatory mechanisms. For example, the catalytic kinase domains of the Tec family kinases are inactive without assembly of the adjacent regulatory domains, whereas the Src kinase domains are autoinhibited by the assembly of similar adjacent regulatory domains. Using molecular dynamics simulations, biochemical assays, and biophysical approaches, we have uncovered an isoleucine residue in the kinase domain of the Tec family member Btk that, when mutated to the closely related leucine, leads to a shift in the conformational equilibrium of the kinase domain toward the active state. The single amino acid mutation results in measureable catalytic activity for the Btk kinase domain in the absence of the regulatory domains. We suggest that this isoleucine side chain in the Tec family kinases acts as a "wedge" that restricts the conformational space available to key regions in the kinase domain, preventing activation until the kinase domain associates with its regulatory subunits and overcomes the energetic barrier to activation imposed by the isoleucine side chain.
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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.