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- PDB-4zlz: Crystal Structure of Bruton's Tyrosine Kinase in complex with a s... -

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Basic information

Entry
Database: PDB / ID: 4zlz
TitleCrystal Structure of Bruton's Tyrosine Kinase in complex with a substituted Cinnoline
ComponentsTyrosine-protein kinase BTK
KeywordsTransferase/Transferase Inhibitor / cytoplasmic tyrosine kinase / transcriptional regulation / nuclear factor-kappaB / 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-4RV / IMIDAZOLE / ISOPROPYL ALCOHOL / Tyrosine-protein kinase BTK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2 Å
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.
History
DepositionMay 1, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 1, 2015Provider: repository / Type: Initial release
Revision 1.1Aug 5, 2015Group: Database references / Other
Revision 1.2Mar 6, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_struct_oper_list
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_oper_list.symmetry_operation

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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)32,0676
Polymers31,5111
Non-polymers5565
Water6,089338
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)72.909, 103.788, 38.032
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21212

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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: 31511.209 Da / Num. of mol.: 1 / Fragment: UNP residues 423-692
Source method: isolated from a genetically manipulated source
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, 343 molecules

#2: Chemical ChemComp-IMD / IMIDAZOLE / Imidazole


Mass: 69.085 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H5N2
#3: Chemical ChemComp-IPA / ISOPROPYL ALCOHOL / 2-PROPANOL / Isopropyl alcohol


Mass: 60.095 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O / Comment: alkaloid*YM
#4: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#5: Chemical ChemComp-4RV / 4-amino-8-(4-methylpyridin-3-yl)cinnoline-3-carboxamide


Mass: 279.297 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H13N5O
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 338 / 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: 2.28 Å3/Da / Density % sol: 46.13 %
Crystal growTemperature: 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 K
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X6A / Wavelength: 1.127 Å
DetectorType: ADSC QUANTUM 270 / Detector: CCD / Date: Jun 28, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.127 Å / Relative weight: 1
ReflectionResolution: 1.95→50 Å / Num. obs: 21777 / % possible obs: 99.2 % / Redundancy: 5.1 % / Rmerge(I) obs: 0.148 / Χ2: 1.101 / Net I/av σ(I): 10.146 / Net I/σ(I): 5.7 / Num. measured all: 111763
Reflection shell

Diffraction-ID: 1 / Rejects: 0

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2% possible all
1.95-1.984.70.65110820.95399.6
1.98-2.025.30.44510690.902100
2.02-2.065.10.51910781.015100
2.06-2.14.70.39510541.24399.5
2.1-2.155.20.37510821.10899.9
2.15-2.25.40.31610621.0799.9
2.2-2.2550.30510991.27799.2
2.25-2.3150.29510561.28999.2
2.31-2.385.50.23311001.084100
2.38-2.465.50.21510591.113100
2.46-2.545.50.19811061.17399.7
2.54-2.655.40.18210741.18299.6
2.65-2.775.10.17110901.26399.5
2.77-2.915.50.1410961.185100
2.91-3.15.50.11610911.067100
3.1-3.335.50.10510951.03399.7
3.33-3.674.30.09410821.19496.8
3.67-4.24.20.09110650.97195.3
4.2-5.295.30.08111411.00399
5.29-5050.10911960.92697.5

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Processing

Software
NameVersionClassification
HKL-2000data reduction
HKL-2000data scaling
REFMAC5.7.0025refinement
PDB_EXTRACT3.15data extraction
RefinementResolution: 2→30 Å / Cor.coef. Fo:Fc: 0.949 / Cor.coef. Fo:Fc free: 0.908 / SU B: 7.641 / SU ML: 0.115 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.199 / ESU R Free: 0.183 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT
RfactorNum. reflection% reflectionSelection details
Rfree0.2408 1014 5.1 %RANDOM
Rwork0.1756 ---
obs0.1788 18910 98.53 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 74.99 Å2 / Biso mean: 21.292 Å2 / Biso min: 8.21 Å2
Baniso -1Baniso -2Baniso -3
1-0.5 Å20 Å20 Å2
2--1.42 Å20 Å2
3----1.92 Å2
Refinement stepCycle: final / Resolution: 2→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2208 0 39 338 2585
Biso mean--24.91 31.32 -
Num. residues----270
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0192317
X-RAY DIFFRACTIONr_bond_other_d0.0320.028
X-RAY DIFFRACTIONr_angle_refined_deg1.2571.9763119
X-RAY DIFFRACTIONr_angle_other_deg0.598316
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.7015269
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.08523.945109
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.52515425
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.1021513
X-RAY DIFFRACTIONr_chiral_restr0.0990.2327
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0211746
LS refinement shellResolution: 2→2.052 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.307 70 -
Rwork0.216 1357 -
all-1427 -
obs--99.37 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.0444-0.04560.13281.51820.15430.7195-0.0098-0.0002-0.0171-0.08570.0656-0.06040.0799-0.0304-0.05580.065-0.01960.00730.0146-0.00490.0402-15.9714-0.5794-9.7449
20.2776-0.979-0.52533.66142.01692.13940.04030.0255-0.0097-0.2519-0.08470.10670.0661-0.21450.04440.1226-0.0379-0.01780.06060.02040.0722-19.49184.7388-4.1726
30.22820.07340.05550.4443-0.01080.6313-0.00540.01350.0111-0.01060.0192-0.02140.04470.0166-0.01380.00530.00080.00420.02210.00640.0216-16.321519.7496-6.2963
40.9617-0.21450.370.1882-0.04961.1592-0.0084-0.00480.10060.01870.0147-0.0619-0.09470.0035-0.00630.01370.00410.00520.00410.00330.0441-15.379531.8847-2.3419
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A389 - 464
2X-RAY DIFFRACTION2A465 - 487
3X-RAY DIFFRACTION3A488 - 591
4X-RAY DIFFRACTION4A592 - 658

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