8S9F

Crystal structure of the kinase domain of Bruton's Tyrosine Kinase bound to dasatinib

Summary for 8S9F

• Entry DOI: 10.2210/pdb8s9f/pdb
• Related: 8GMB 8S93
• Descriptor: Tyrosine-protein kinase BTK, N-(2-CHLORO-6-METHYLPHENYL)-2-({6-[4-(2-HYDROXYETHYL)PIPERAZIN-1-YL]-2-METHYLPYRIMIDIN-4-YL}AMINO)-1,3-THIAZOLE-5-CARBOXAMIDE (3 entities in total)
• Functional Keywords: bruton's tyrosine kinase, atp-binding, protein phosphorylation, transferase
• Biological source: Mus musculus (house mouse)
• Total number of polymer chains: 2
• Total formula weight: 65548.00

Authors

Lin, D.Y.,Andreotti, A.H. (deposition date: 2023-03-28, release date: 2023-08-16, Last modification date: 2024-01-31)

Primary citation

Lin, D.Y.,Kueffer, L.E.,Juneja, P.,Wales, T.E.,Engen, J.R.,Andreotti, A.H.
Conformational heterogeneity of the BTK PHTH domain drives multiple regulatory states.
Elife, 12:-, 2024

PubMed 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.

PubMed: 38189455
DOI: 10.7554/eLife.89489

Experimental method

X-RAY DIFFRACTION (2.6 Å)