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- PDB-5vgo: Bruton's tyrosine kinase (BTK) with compound G-744 -

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Basic information

Entry
Database: PDB / ID: 5vgo
TitleBruton's tyrosine kinase (BTK) with compound G-744
ComponentsTyrosine-protein kinase BTK
KeywordsTransferase/Transferase Inhibitor / protein kinase / inhibitor / Transferase-Transferase Inhibitor complex
Function / homology
Function and homology information


regulation of B cell cytokine production / proteoglycan catabolic process / monocyte proliferation / positive regulation of interleukin-17A production / regulation of B cell apoptotic process / eosinophil homeostasis / positive regulation of type III hypersensitivity / B cell affinity maturation / histamine secretion by mast cell / positive regulation of synoviocyte proliferation ...regulation of B cell cytokine production / proteoglycan catabolic process / monocyte proliferation / positive regulation of interleukin-17A production / regulation of B cell apoptotic process / eosinophil homeostasis / positive regulation of type III hypersensitivity / B cell affinity maturation / histamine secretion by mast cell / positive regulation of synoviocyte proliferation / neutrophil homeostasis / cellular response to molecule of fungal origin / positive regulation of type I hypersensitivity / cellular response to interleukin-7 / MyD88 deficiency (TLR2/4) / MyD88-dependent toll-like receptor signaling pathway / IRAK4 deficiency (TLR2/4) / MyD88:MAL(TIRAP) cascade initiated on plasma membrane / positive regulation of B cell differentiation / positive regulation of NLRP3 inflammasome complex assembly / phospholipase activator activity / negative regulation of interleukin-10 production / B cell activation / negative regulation of B cell proliferation / Fc-epsilon receptor signaling pathway / phosphatidylinositol-3,4,5-trisphosphate binding / phospholipase binding / mesoderm development / positive regulation of immunoglobulin production / RHO GTPases Activate WASPs and WAVEs / positive regulation of phagocytosis / positive regulation of B cell proliferation / cell maturation / FCERI mediated Ca+2 mobilization / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / apoptotic signaling pathway / calcium-mediated signaling / FCGR3A-mediated phagocytosis / B cell receptor signaling pathway / non-specific protein-tyrosine kinase / non-membrane spanning protein tyrosine kinase activity / G beta:gamma signalling through BTK / Regulation of actin dynamics for phagocytic cup formation / cellular response to reactive oxygen species / positive regulation of interleukin-6 production / peptidyl-tyrosine phosphorylation / G alpha (12/13) signalling events / positive regulation of tumor necrosis factor production / DAP12 signaling / positive regulation of NF-kappaB transcription factor activity / ER-Phagosome pathway / T cell receptor signaling pathway / cytoplasmic vesicle / G alpha (q) signalling events / protein tyrosine kinase activity / Potential therapeutics for SARS / response to lipopolysaccharide / adaptive immune response / intracellular signal transduction / membrane raft / protein phosphorylation / innate immune response / perinuclear region of cytoplasm / ATP binding / identical protein binding / metal ion binding / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Tyrosine-protein kinase BTK, SH3 domain / Zinc finger, Btk motif / BTK motif / Zinc finger Btk-type profile. / Bruton's tyrosine kinase Cys-rich motif / PH domain / PH domain profile. / Pleckstrin homology domain. / Pleckstrin homology domain / SH3 domain ...Tyrosine-protein kinase BTK, SH3 domain / Zinc finger, Btk motif / BTK motif / Zinc finger Btk-type profile. / Bruton's tyrosine kinase Cys-rich motif / PH domain / PH domain profile. / Pleckstrin homology domain. / Pleckstrin homology domain / SH3 domain / SH2 domain / Src homology 2 (SH2) domain profile. / Src homology 2 domains / Src homology 3 domains / SH2 domain / SH2 domain superfamily / SH3-like domain superfamily / Src homology 3 (SH3) domain profile. / SH3 domain / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / PH-like domain superfamily / Tyrosine-protein kinase, active site / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-9B1 / Tyrosine-protein kinase BTK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.621 Å
AuthorsYu, C. / Eigenbrot, C.
CitationJournal: ACS Med Chem Lett / Year: 2017
Title: Discovery of Potent and Selective Tricyclic Inhibitors of Bruton's Tyrosine Kinase with Improved Druglike Properties.
Authors: Wang, X. / Barbosa, J. / Blomgren, P. / Bremer, M.C. / Chen, J. / Crawford, J.J. / Deng, W. / Dong, L. / Eigenbrot, C. / Gallion, S. / Hau, J. / Hu, H. / Johnson, A.R. / Katewa, A. / Kropf, ...Authors: Wang, X. / Barbosa, J. / Blomgren, P. / Bremer, M.C. / Chen, J. / Crawford, J.J. / Deng, W. / Dong, L. / Eigenbrot, C. / Gallion, S. / Hau, J. / Hu, H. / Johnson, A.R. / Katewa, A. / Kropf, J.E. / Lee, S.H. / Liu, L. / Lubach, J.W. / Macaluso, J. / Maciejewski, P. / Mitchell, S.A. / Ortwine, D.F. / DiPaolo, J. / Reif, K. / Scheerens, H. / Schmitt, A. / Wong, H. / Xiong, J.M. / Xu, J. / Zhao, Z. / Zhou, F. / Currie, K.S. / Young, W.B.
History
DepositionApr 11, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 5, 2017Provider: repository / Type: Initial release
Revision 1.1Oct 4, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Tyrosine-protein kinase BTK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,9338
Polymers31,7891
Non-polymers1,1447
Water4,900272
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)108.314, 108.314, 42.570
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number169
Space group name H-MP61

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Components

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Protein , 1 types, 1 molecules A

#1: Protein Tyrosine-protein kinase BTK / Agammaglobulinemia tyrosine kinase / ATK / B-cell progenitor kinase / BPK / Bruton tyrosine kinase


Mass: 31788.592 Da / Num. of mol.: 1 / Fragment: UNP residues 427-691
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BTK, AGMX1, ATK, BPK / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q06187, non-specific protein-tyrosine kinase

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Non-polymers , 5 types, 279 molecules

#2: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical ChemComp-PG0 / 2-(2-METHOXYETHOXY)ETHANOL / PEG 6000 / 2-(2-Methoxyethoxy)ethanol


Mass: 120.147 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C5H12O3 / Comment: inhibitor, precipitant*YM
#5: Chemical ChemComp-9B1 / 2-[2-(hydroxymethyl)-3-{1-methyl-6-oxo-5-[(pyrimidin-4-yl)amino]-1,6-dihydropyridin-3-yl}phenyl]-6,6-dimethyl-3,4,6,7-tetrahydro-2H-cyclopenta[4,5]thieno[2,3-c]pyridin-1(5H)-one


Mass: 527.637 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H29N5O3S
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 272 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.27 Å3/Da / Density % sol: 45.76 % / Description: rods
Crystal growTemperature: 286 K / Method: vapor diffusion, hanging drop / pH: 5.5
Details: reservoir 0.1 M LiSO4, 0.1 M citric acid pH 5.5, 6% PEG 10K, 0.4% beta-octylglucoside protein 8 mg/mL 10 mM Tris 8.5, 0.1 M NaCl, 0.5 mM TCEP, G-744 made 0.5 mM using 10 mM DMSO stock drop 1:2 protein/reservoir.

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Data collection

DiffractionMean temperature: 110 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-2 / Wavelength: 0.9795 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 14, 2014
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 1.62→46.901 Å / Num. obs: 36419 / % possible obs: 99 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 10.1 % / Biso Wilson estimate: 22.8 Å2 / Rsym value: 0.0477 / Net I/σ(I): 28.6
Reflection shellResolution: 1.62→1.68 Å / Redundancy: 10 % / Mean I/σ(I) obs: 2.5 / Num. unique obs: 2733 / Rsym value: 0.929 / % possible all: 99

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
XDSdata reduction
Aimlessdata scaling
REFMACphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4RX5

4rx5


Resolution: 1.621→46.901 Å / SU ML: 0.18 / Cross valid method: FREE R-VALUE / σ(F): 1.89 / Phase error: 18.21
RfactorNum. reflection% reflectionSelection details
Rfree0.1843 1873 5.14 %template set
Rwork0.161 ---
obs0.1622 36418 99.88 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.621→46.901 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2175 0 76 272 2523
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0062399
X-RAY DIFFRACTIONf_angle_d1.0523251
X-RAY DIFFRACTIONf_dihedral_angle_d13.928927
X-RAY DIFFRACTIONf_chiral_restr0.042335
X-RAY DIFFRACTIONf_plane_restr0.004409
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.621-1.66480.26521500.24042583X-RAY DIFFRACTION99
1.6648-1.71380.25121480.21282639X-RAY DIFFRACTION100
1.7138-1.76910.23981470.19522652X-RAY DIFFRACTION100
1.7691-1.83230.22741500.18842626X-RAY DIFFRACTION100
1.8323-1.90570.23461330.17682666X-RAY DIFFRACTION100
1.9057-1.99240.20621540.17052607X-RAY DIFFRACTION100
1.9924-2.09750.19391320.16462670X-RAY DIFFRACTION100
2.0975-2.22890.20331500.1612646X-RAY DIFFRACTION100
2.2289-2.4010.2081350.16062657X-RAY DIFFRACTION100
2.401-2.64260.19481340.17152705X-RAY DIFFRACTION100
2.6426-3.02490.18841560.16942641X-RAY DIFFRACTION100
3.0249-3.81080.16731480.14492684X-RAY DIFFRACTION100
3.8108-46.9210.14271360.14452769X-RAY DIFFRACTION100

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