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- PDB-4y95: Crystal structure of the kinase domain of Bruton's tyrosine kinas... -

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Basic information

Entry
Database: PDB / ID: 4y95
TitleCrystal structure of the kinase domain of Bruton's tyrosine kinase with mutations in the activation loop
ComponentsNon-specific protein-tyrosine kinaseNon-receptor tyrosine kinase
KeywordsTRANSFERASE / Btk / kinase domain
Function / homology
Function and homology information


FCERI mediated Ca+2 mobilization / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / Regulation of actin dynamics for phagocytic cup formation / RHO GTPases Activate WASPs and WAVEs / DAP12 signaling / B cell affinity maturation / cellular response to interleukin-7 / G alpha (12/13) signalling events / G beta:gamma signalling through BTK / G alpha (q) signalling events ...FCERI mediated Ca+2 mobilization / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / Regulation of actin dynamics for phagocytic cup formation / RHO GTPases Activate WASPs and WAVEs / DAP12 signaling / B cell affinity maturation / cellular response to interleukin-7 / G alpha (12/13) signalling events / G beta:gamma signalling through BTK / G alpha (q) signalling events / negative regulation of cytokine production / positive regulation of NLRP3 inflammasome complex assembly / phospholipase activator activity / negative regulation of B cell proliferation / phosphatidylinositol-3,4,5-trisphosphate binding / phospholipase binding / cell maturation / B cell receptor signaling pathway / non-specific protein-tyrosine kinase / non-membrane spanning protein tyrosine kinase activity / T cell receptor signaling pathway / cytoplasmic vesicle / adaptive immune response / intracellular signal transduction / membrane raft / phosphorylation / ATP binding / identical protein binding / metal ion binding / nucleus / plasma membrane / cytosol
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 / SH2 domain / Src homology 3 domains / 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-746 / BETA-MERCAPTOETHANOL / Tyrosine-protein kinase
Similarity search - Component
Biological speciesBos taurus (cattle)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.599 Å
AuthorsWang, Q. / Rosen, C.E. / Kuriyan, J.
Funding support United States, 3items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)AI 091580 United States
Howard Hughes Medical Institute (HHMI) United States
Cancer Research Institute United States
CitationJournal: Elife / Year: 2015
Title: Autoinhibition of Bruton's tyrosine kinase (Btk) and activation by soluble inositol hexakisphosphate.
Authors: Wang, Q. / Vogan, E.M. / Nocka, L.M. / Rosen, C.E. / Zorn, J.A. / Harrison, S.C. / Kuriyan, J.
History
DepositionFeb 16, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 18, 2015Provider: repository / Type: Initial release
Revision 1.1Sep 27, 2017Group: Advisory / Author supporting evidence ...Advisory / Author supporting evidence / Derived calculations / Source and taxonomy
Category: entity_src_gen / pdbx_audit_support ...entity_src_gen / pdbx_audit_support / pdbx_struct_oper_list / pdbx_validate_close_contact
Item: _entity_src_gen.pdbx_alt_source_flag / _pdbx_audit_support.funding_organization / _pdbx_struct_oper_list.symmetry_operation
Revision 1.2Nov 20, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Feb 28, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Non-specific protein-tyrosine kinase
B: Non-specific protein-tyrosine kinase
C: Non-specific protein-tyrosine kinase
D: Non-specific protein-tyrosine kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)128,17821
Polymers124,1794
Non-polymers3,99917
Water17,439968
1
A: Non-specific protein-tyrosine kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,7954
Polymers31,0451
Non-polymers7503
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Non-specific protein-tyrosine kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,2416
Polymers31,0451
Non-polymers1,1965
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: Non-specific protein-tyrosine kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,1495
Polymers31,0451
Non-polymers1,1044
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
4
D: Non-specific protein-tyrosine kinase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,9936
Polymers31,0451
Non-polymers9485
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)50.929, 79.067, 79.178
Angle α, β, γ (deg.)90.730, 89.900, 89.990
Int Tables number1
Space group name H-MP1

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Components

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Protein , 1 types, 4 molecules ABCD

#1: Protein
Non-specific protein-tyrosine kinase / Non-receptor tyrosine kinase


Mass: 31044.742 Da / Num. of mol.: 4 / Fragment: kinase domain (UNP 395-659)
Mutation: L542M, S543T, Y545F, V555T, S557T, R562K, S564A, P565S, and Y617P
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Bos taurus (cattle) / Gene: BTK / Production host: Escherichia coli (E. coli)
References: UniProt: Q3ZC95, non-specific protein-tyrosine kinase

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Non-polymers , 5 types, 985 molecules

#2: Chemical
ChemComp-746 / 4-tert-butyl-N-[2-methyl-3-(4-methyl-6-{[4-(morpholin-4-ylcarbonyl)phenyl]amino}-5-oxo-4,5-dihydropyrazin-2-yl)phenyl]benzamide / CGI1746


Mass: 579.689 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C34H37N5O4
#3: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical ChemComp-BME / BETA-MERCAPTOETHANOL / 2-Mercaptoethanol


Mass: 78.133 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6OS
#5: Chemical ChemComp-PE4 / 2-{2-[2-(2-{2-[2-(2-ETHOXY-ETHOXY)-ETHOXY]-ETHOXY}-ETHOXY)-ETHOXY]-ETHOXY}-ETHANOL / POLYETHYLENE GLYCOL PEG4000 / Polyethylene glycol


Mass: 354.436 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C16H34O8 / Comment: precipitant*YM
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 968 / 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: 2.57 Å3/Da / Density % sol: 52.11 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 0.2 M ammonium citrate dibasic, 20% PEG 3350 / PH range: 6.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 8.2.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jul 16, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.54→50 Å / Num. obs: 173792 / % possible obs: 95.3 % / Redundancy: 2 % / Biso Wilson estimate: 18.03 Å2 / Rmerge(I) obs: 0.031 / Rpim(I) all: 0.031 / Rrim(I) all: 0.044 / Χ2: 0.928 / Net I/av σ(I): 20.563 / Net I/σ(I): 14.8 / Num. measured all: 339235
Reflection shell

Diffraction-ID: 1 / Rejects: 0

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allCC1/2Rpim(I) allRrim(I) allΧ2% possible all
1.54-1.61.90.238150900.860.2380.3360.65182.9
1.6-1.6620.183171760.9070.1830.2590.7194.6
1.66-1.7320.134174320.9470.1340.1890.77495.3
1.73-1.8320.097174780.9730.0970.1370.88295.7
1.83-1.9420.075175030.9810.0750.1061.01696.1
1.94-2.0920.054176740.9890.0540.0761.11196.6
2.09-2.320.043177270.9920.0430.061.14497
2.3-2.6320.035177990.9940.0350.0491.0997.6
2.63-3.321.90.029178930.9960.0290.0411.05198
3.32-501.90.021180200.9970.0210.0290.78598.8

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Processing

Software
NameVersionClassification
PHENIXrefinement
HKL-2000data scaling
PDB_EXTRACT3.15data extraction
HKL-2000data reduction
RefinementResolution: 1.599→39.586 Å / SU ML: 0.14 / Cross valid method: FREE R-VALUE / σ(F): 1.98 / Phase error: 16.68 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1838 2009 1.28 %
Rwork0.1546 155551 -
obs0.1549 157560 96.44 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 120.23 Å2 / Biso mean: 26.3631 Å2 / Biso min: 10.3 Å2
Refinement stepCycle: final / Resolution: 1.599→39.586 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8597 0 474 968 10039
Biso mean--32.37 34.84 -
Num. residues----1063
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.019366
X-RAY DIFFRACTIONf_angle_d1.4812682
X-RAY DIFFRACTIONf_chiral_restr0.0731330
X-RAY DIFFRACTIONf_plane_restr0.0061595
X-RAY DIFFRACTIONf_dihedral_angle_d15.4823552
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 14

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.5989-1.63890.2561430.1867106141075792
1.6389-1.68320.23271450.1788109941113995
1.6832-1.73270.15771320.17109091104195
1.7327-1.78870.1911340.1586110431117796
1.7887-1.85260.18111400.1589110921123296
1.8526-1.92680.14791510.1613110281117996
1.9268-2.01450.21971520.1519110801123297
2.0145-2.12070.2081290.1536111991132897
2.1207-2.25350.17841450.1484111661131197
2.2535-2.42750.20741470.1466112121135997
2.4275-2.67170.15621520.1461112341138698
2.6717-3.05820.15741470.1515112701141798
3.0582-3.85250.1631350.1483113171145298
3.8525-39.59790.20831570.1604113931155099

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