Database of articles cited by EMDB/PDB/SASBDB data

Keywords
Structure methods	All X-ray diffraction NMR electron microscopy small angle scattering neutron diffraction fiber diffraction powder diffraction infrared spectroscopy EPR fluorescence transfer theoretical model Hybrid
Author
Journal
IF	>30 >20 >10 >5 all

Title	Conformational heterogeneity of the BTK PHTH domain drives multiple regulatory states.
Journal, issue, pages	Elife, Vol. 12, Year 2024
Publish date	Jan 8, 2024
Authors	David Yin-Wei Lin / Lauren E Kueffer / Puneet Juneja / Thomas E Wales / John R Engen / Amy H Andreotti /
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 ...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.
External links	Elife / PubMed:38189455 / PubMed Central
Methods	EM (single particle) / X-ray diffraction
Resolution	2.1 - 6.36 Å
Structure data	EMDB-40585: CryoEM reconstruction of full-length Btk (class 0) Method: EM (single particle) / Resolution: 5.48 Å EMDB-40586: CryoEM reconstruction of full-length Btk (class 1) Method: EM (single particle) / Resolution: 6.36 Å EMDB-40587: CryoEM reconstruction of full-length Btk (class 3) Method: EM (single particle) / Resolution: 5.56 Å PDB-8gmb: Crystal structure of the full-length Bruton's tyrosine kinase (PH-TH domain not visible) Method: X-RAY DIFFRACTION / Resolution: 3.4 Å PDB-8s93: Crystal structure of the PH-TH/kinase complex of Bruton's tyrosine kinase Method: X-RAY DIFFRACTION / Resolution: 2.1 Å PDB-8s9f: Crystal structure of the kinase domain of Bruton's Tyrosine Kinase bound to dasatinib Method: X-RAY DIFFRACTION / Resolution: 2.6 Å
Chemicals	ChemComp-9AJ: 2-[3'-(hydroxymethyl)-1-methyl-5-({5-[(2S)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl}amino)-6-oxo[1,6-dihydro[3,4'-bipyridine]]-2'-yl]-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one ChemComp-ZN: Unknown entry ChemComp-GOL: GLYCEROL / Glycerol ChemComp-HOH: WATER / Water ChemComp-1N1: N-(2-CHLORO-6-METHYLPHENYL)-2-({6-[4-(2-HYDROXYETHYL)PIPERAZIN-1-YL]-2-METHYLPYRIMIDIN-4-YL}AMINO)-1,3-THIAZOLE-5-CARBOXAMIDE / medication*YM / Dasatinib
Source	mus musculus (house mouse)
Keywords	TRANSFERASE / ATP-binding / Lipid-binding / transcription regulation / immunity / Bruton's tyrosine kinase / Non-receptor tyrosine kinase / complex / protein phosphorylation