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- PDB-4zly: Crystal Structure of Bruton's Tyrosine Kinase bound to a Cinnolin... -

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Entry
Database: PDB / ID: 4zly
TitleCrystal Structure of Bruton's Tyrosine Kinase bound to a Cinnoline Fragment
ComponentsTyrosine-protein kinase BTK
KeywordsTransferase/Transferase Inhibitor / cytoplasmic tyrosine kinase / transcriptional regulation / nuclear factor-kappaB / Transferase-Transferase Inhibitor complex
Function / homologySH2 domain / PH domain profile. / MyD88:MAL(TIRAP) cascade initiated on plasma membrane / Pleckstrin homology domain / ER-Phagosome pathway / Zinc finger Btk-type profile. / Protein kinase domain profile. / SH3 domain / Zinc finger, Btk motif / Src homology 3 (SH3) domain profile. ...SH2 domain / PH domain profile. / MyD88:MAL(TIRAP) cascade initiated on plasma membrane / Pleckstrin homology domain / ER-Phagosome pathway / Zinc finger Btk-type profile. / Protein kinase domain profile. / SH3 domain / Zinc finger, Btk motif / Src homology 3 (SH3) domain profile. / Protein kinase-like domain superfamily / Src homology 2 (SH2) domain profile. / SH3 domain / Tyrosine protein kinases specific active-site signature. / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein kinases ATP-binding region signature. / Protein tyrosine kinase / BTK motif / PH domain / Tyrosine-protein kinase, active site / Regulation of actin dynamics for phagocytic cup formation / Protein kinase domain / IRAK4 deficiency (TLR2/4) / SH2 domain superfamily / SH3-like domain superfamily / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / Tyrosine-protein kinase BTK, SH3 domain / PH-like domain superfamily / RHO GTPases Activate WASPs and WAVEs / G beta:gamma signalling through BTK / Tyrosine-protein kinase, catalytic domain / MyD88 deficiency (TLR2/4) / G alpha (12/13) signalling events / G alpha (q) signalling events / FCERI mediated Ca+2 mobilization / DAP12 signaling / Protein kinase, ATP binding site / SH2 domain / regulation of B cell cytokine production / positive regulation of type III hypersensitivity / histamine secretion by mast cell / regulation of B cell apoptotic process / B cell affinity maturation / cellular response to molecule of fungal origin / negative regulation of cytokine production / positive regulation of B cell differentiation / cellular response to interleukin-7 / positive regulation of type I hypersensitivity / B cell activation / mesoderm development / negative regulation of B cell proliferation / phosphatidylinositol-3,4,5-trisphosphate binding / mast cell granule / cell maturation / calcium-mediated signaling / MyD88-dependent toll-like receptor signaling pathway / apoptotic signaling pathway / cellular response to reactive oxygen species / I-kappaB kinase/NF-kappaB signaling / non-specific protein-tyrosine kinase / peptidyl-tyrosine autophosphorylation / Fc-epsilon receptor signaling pathway / non-membrane spanning protein tyrosine kinase activity / peptidyl-tyrosine phosphorylation / B cell receptor signaling pathway / adaptive immune response / T cell receptor signaling pathway / cytoplasmic vesicle / positive regulation of NF-kappaB transcription factor activity / protein tyrosine kinase activity / intracellular signal transduction / membrane raft / innate immune response / protein phosphorylation / perinuclear region of cytoplasm / ATP binding / identical protein binding / plasma membrane / metal ion binding / nucleus / cytosol / cytoplasm / Tyrosine-protein kinase BTK
Function and homology information
Specimen sourceHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / 1.65 Å resolution
AuthorsDougan, D.R.
CitationJournal: J.Med.Chem. / Year: 2015
Title: Fragment-Based Discovery of a Small Molecule Inhibitor of Bruton's Tyrosine Kinase.
Authors: Smith, C.R. / Dougan, D.R. / Komandla, M. / Kanouni, T. / Knight, B. / Lawson, J.D. / Sabat, M. / Taylor, E.R. / Vu, P. / Wyrick, C.
Validation Report
SummaryFull reportAbout validation report
DateDeposition: May 1, 2015 / Release: Jul 1, 2015
RevisionDateData content typeGroupProviderType
1.0Jul 1, 2015Structure modelrepositoryInitial release
1.1Aug 5, 2015Structure modelDatabase references / Other

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Tyrosine-protein kinase BTK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,9766
Polyers31,5111
Non-polymers4655
Water6,882382
1


TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
γ
α
β
Length a, b, c (Å)72.864, 104.458, 38.047
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP 21 21 2

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Components

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Protein/peptide , 1 types, 1 molecules A

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


Mass: 31511.209 Da / Num. of mol.: 1 / Fragment: UNP residues 423-692 / Source: (gene. exp.) Homo sapiens (human) / Gene: BTK, AGMX1, ATK, BPK / Production host: unidentified baculovirus / Strain (production host): sf9
References: UniProt: Q06187, non-specific protein-tyrosine kinase

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Non-polymers , 5 types, 387 molecules

#2: Chemical ChemComp-IMD / IMIDAZOLE


Mass: 69.085 Da / Num. of mol.: 2 / Formula: C3H5N2 / Imidazole
#3: Chemical ChemComp-IPA / ISOPROPYL ALCOHOL / 2-PROPANOL


Mass: 60.095 Da / Num. of mol.: 1 / Formula: C3H8O / Isopropyl alcohol
#4: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Formula: C2H6OS / Dimethyl sulfoxide / Comment: DMSO (precipitant for crystallization) *YM
#5: Chemical ChemComp-4RU / 4-aminocinnoline-3-carboxamide


Mass: 188.186 Da / Num. of mol.: 1 / Formula: C9H8N4O
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 382 / Formula: H2O / Water

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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: 2.3 / Density percent sol: 46.46 %
Crystal growTemp: 277 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 10% polyethylene glycol 4000, 20% glycerol, 0.1M imidazole/MES, pH 6.5, 0.12M alcohol mixture

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Data collection

DiffractionMean temperature: 100 kelvins
SourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 0.976 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Collection date: May 6, 2011
RadiationDiffraction protocol: SINGLE WAVELENGTH / Monochromatic or laue m l: M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976 Å / Relative weight: 1
ReflectionD resolution high: 1.65 Å / D resolution low: 50 Å / Number obs: 33742 / NetI over sigmaI: 10.33 / Redundancy: 5.9 % / Percent possible obs: 98.5

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Processing

Software
NameVersionClassification
REFMAC5.7.0025refinement
HKL-2000data reduction
HKL-2000data scaling
PDB_EXTRACT3.15data extraction
RefineCorrelation coeff Fo to Fc: 0.961 / Correlation coeff Fo to Fc free: 0.946 / Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT / Overall SU B: 3.058 / Overall SU ML: 0.054 / R Free selection details: RANDOM / Cross valid method: THROUGHOUT / Sigma F: 0 / Overall ESU R: 0.094 / Overall ESU R Free: 0.093 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Solvent computationSolvent ion probe radii: 0.8 Å / Solvent shrinkage radii: 0.8 Å / Solvent vdw probe radii: 1.2 Å / Solvent model details: MASK
Displacement parametersB iso max: 67.72 Å2 / B iso mean: 16.117 Å2 / B iso min: 3.87 Å2 / Aniso B11: 0.48 Å2 / Aniso B12: 0 Å2 / Aniso B13: 0 Å2 / Aniso B22: -0.31 Å2 / Aniso B23: 0 Å2 / Aniso B33: -0.17 Å2
Least-squares processR factor R free: 0.1965 / R factor R work: 0.163 / R factor obs: 0.1647 / Highest resolution: 1.65 Å / Lowest resolution: 35 Å / Number reflection R free: 1780 / Number reflection obs: 33742 / Percent reflection R free: 5 / Percent reflection obs: 99.22
Refine hist #finalHighest resolution: 1.65 Å / Lowest resolution: 35 Å / B iso mean ligand: 19.41 / B iso mean solvent: 28.45 / Number residues total: 270
Number of atoms included #finalProtein: 2208 / Nucleic acid: 0 / Ligand: 32 / Solvent: 382 / Total: 2622
Refine LS restraints
Refine IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0192349
X-RAY DIFFRACTIONr_angle_refined_deg1.2971.9713166
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.8755.000269
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.14124.211114
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.20615.000441
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.56715.00013
X-RAY DIFFRACTIONr_chiral_restr0.0970.200341
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0211757
Refine LS shellHighest resolution: 1.65 Å / R factor R free: 0.259 / R factor R work: 0.223 / Lowest resolution: 1.693 Å / Number reflection R free: 131 / Number reflection R work: 2411 / Number reflection all: 2542 / Total number of bins used: 20 / Percent reflection obs: 98.87
Refine TLS

Method: refined / Refine ID: X-RAY DIFFRACTION

IDL11L12L13L22L23L33S11S12S13S21S22S23S31S32S33T11T12T13T22T23T33Origin xOrigin yOrigin z
10.09190.0869-0.03871.21680.36260.2254-0.0212-0.0333-0.00610.06130.0704-0.03460.07230.0386-0.04920.06290.0091-0.00350.02310.00650.035916.2752-0.54699.6499
20.34270.02580.17212.3845-1.02661.0937-0.06510.0075-0.03320.11330.0232-0.17260.04100.05820.04190.05950.0247-0.00960.0172-0.00980.023420.16604.73864.0585
30.38640.0831-0.00680.33450.00570.84040.0196-0.0471-0.01850.0019-0.0040-0.00300.03420.0323-0.01560.00340.0013-0.00290.0164-0.00100.002916.526919.89756.2967
41.07850.13270.10260.36630.00380.7795-0.0029-0.01710.0997-0.02620.01640.0213-0.09210.0019-0.01340.0197-0.00280.00170.0055-0.00750.019915.495832.07062.3389
Refine TLS group

Beg auth asym ID: A / End auth asym ID: A / Refine ID: X-RAY DIFFRACTION

IDBeg auth seq IDEnd auth seq IDRefine TLS ID
13894641
24654872
34885913
45926584

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