ArticleeLife2024
Conformational heterogeneity of the BTK PHTH domain drives multiple regulatory states.
Article in eLife, 2024. 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.
- Two-step mechanism of Bruton's tyrosine kinase membrane recruitment and activation.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Unconventional binding of calmodulin to CHK2 kinase inhibits catalytic activity.The Biochemical journal · 2025Article
- Two-Step Mechanism of Bruton's Tyrosine Kinase Membrane Recruitment and Activation.bioRxiv : the preprint server for biology · 2025Article
- BTK autoinhibition analyzed by high-throughput swaps of SH2 domains.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Modulating the Binding Kinetics of Bruton's Tyrosine Kinase Inhibitors through Transition-State Effects.Journal of the American Chemical Society · 2025Article
- Membrane-dependent assembly of Bruton's tyrosine kinase mediated by the Proline-rich region and SH3 domain.Protein science : a publication of the Protein Society · 2025Article
- Conditional requirement for dimerization of the membrane-binding module for BTK signaling in lymphocyte cell lines.Science signaling · 2025Article
- Article
- Non-Receptor Tyrosine Kinases: Their Structure and Mechanistic Role in Tumor Progression and Resistance.Cancers · 2024Review
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
Full-length Bruton's tyrosine kinase (BTK) has been refractory to structural analysis. The nearest full-length structure of BTK to date consists of the autoinhibited SH3-SH2-kinase core. Precisely how the BTK N-terminal domains (the Pleckstrin homology/Tec homology [PHTH] domain and proline-rich regions [PRR] contain linker) contribute to BTK regulation remains unclear. We have produced crystals of full-length BTK for the first time but despite efforts to stabilize the autoinhibited state, the diffraction data still reveal only the SH3-SH2-kinase core with no electron density visible for the PHTH-PRR segment. Cryo-electron microscopy (cryoEM) data of full-length BTK, on the other hand, provide the first view of the PHTH domain within full-length BTK. CryoEM reconstructions support conformational heterogeneity in the PHTH-PRR region wherein the globular PHTH domain adopts a range of states arrayed around the autoinhibited SH3-SH2-kinase core. On the way to activation, disassembly of the SH3-SH2-kinase core opens a new autoinhibitory site on the kinase domain for PHTH domain binding that is ultimately released upon interaction of PHTH with phosphatidylinositol (3,4,5)-trisphosphate. Membrane-induced dimerization activates BTK and we present here a crystal structure of an activation loop swapped BTK kinase domain dimer that likely represents the conformational state leading to trans-autophosphorylation. Together, these data provide the first structural elucidation of full-length BTK and allow a deeper understanding of allosteric control over the BTK kinase domain during distinct stages of activation.
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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 Socratic graph.