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- PDB-6ep9: Crystal structure of BTK kinase domain complexed with N-[2-methyl... -

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Basic information

Entry
Database: PDB / ID: 6ep9
TitleCrystal structure of BTK kinase domain complexed with N-[2-methyl-3-[4-methyl-6-[4-(4-methylpiperazine-1-carbonyl)anilino]-5-oxo-pyrazin-2-yl]phenyl]-4-(1-piperidyl)benzamide
ComponentsTyrosine-protein kinase BTK
KeywordsTRANSFERASE / KINASE-INHIBITOR COMPLEX
Function / homology
Function and homology information


regulation of B cell cytokine production / regulation of B cell apoptotic process / monocyte proliferation / positive regulation of interleukin-17A production / eosinophil homeostasis / proteoglycan catabolic process / positive regulation of type III hypersensitivity / B cell affinity maturation / positive regulation of synoviocyte proliferation / histamine secretion by mast cell ...regulation of B cell cytokine production / regulation of B cell apoptotic process / monocyte proliferation / positive regulation of interleukin-17A production / eosinophil homeostasis / proteoglycan catabolic process / positive regulation of type III hypersensitivity / B cell affinity maturation / positive regulation of synoviocyte proliferation / histamine secretion by mast cell / neutrophil homeostasis / positive regulation of cGAS/STING signaling pathway / cellular response to molecule of fungal origin / positive regulation of type I hypersensitivity / MyD88 deficiency (TLR2/4) / cellular response to interleukin-7 / IRAK4 deficiency (TLR2/4) / MyD88-dependent toll-like receptor signaling pathway / MyD88:MAL(TIRAP) cascade initiated on plasma membrane / positive regulation of B cell differentiation / positive regulation of immunoglobulin production / phospholipase activator activity / negative regulation of interleukin-10 production / negative regulation of B cell proliferation / positive regulation of NLRP3 inflammasome complex assembly / Fc-epsilon receptor signaling pathway / mesoderm development / phosphatidylinositol-3,4,5-trisphosphate binding / B cell activation / RHO GTPases Activate WASPs and WAVEs / phospholipase binding / cell maturation / positive regulation of B cell proliferation / FCERI mediated Ca+2 mobilization / positive regulation of phagocytosis / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / peptidyl-tyrosine phosphorylation / cellular response to reactive oxygen species / B cell receptor signaling pathway / non-membrane spanning protein tyrosine kinase activity / FCGR3A-mediated phagocytosis / non-specific protein-tyrosine kinase / apoptotic signaling pathway / calcium-mediated signaling / positive regulation of NF-kappaB transcription factor activity / Regulation of actin dynamics for phagocytic cup formation / positive regulation of interleukin-6 production / G beta:gamma signalling through BTK / positive regulation of tumor necrosis factor production / DAP12 signaling / G alpha (12/13) signalling events / T cell receptor signaling pathway / ER-Phagosome pathway / cytoplasmic vesicle / protein tyrosine kinase activity / response to lipopolysaccharide / G alpha (q) signalling events / Potential therapeutics for SARS / adaptive immune response / positive regulation of canonical NF-kappaB signal transduction / intracellular signal transduction / membrane raft / innate immune response / perinuclear region of cytoplasm / zinc ion binding / ATP binding / identical protein binding / nucleus / plasma membrane / cytoplasm / 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 ...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 / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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-BNB / Tyrosine-protein kinase BTK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.01 Å
AuthorsKuglstatter, A. / Wong, A.
CitationJournal: J.Comput.Aided Mol.Des. / Year: 2019
Title: Water molecules in protein-ligand interfaces. Evaluation of software tools and SAR comparison.
Authors: Nittinger, E. / Gibbons, P. / Eigenbrot, C. / Davies, D.R. / Maurer, B. / Yu, C.L. / Kiefer, J.R. / Kuglstatter, A. / Murray, J. / Ortwine, D.F. / Tang, Y. / Tsui, V.
History
DepositionOct 11, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 22, 2018Provider: repository / Type: Initial release
Revision 1.1Feb 27, 2019Group: Data collection / Database references / Category: citation / citation_author / pdbx_database_proc
Item: _citation.journal_abbrev / _citation.journal_id_CSD ..._citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Mar 20, 2019Group: Data collection / Database references / Category: citation / citation_author / pdbx_database_proc
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.3May 8, 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

Downloads & links

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Assembly

Deposited unit
A: Tyrosine-protein kinase BTK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,1412
Polymers32,5211
Non-polymers6201
Water3,405189
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area12620 Å2
MethodPISA
Unit cell
Length a, b, c (Å)72.408, 106.948, 38.126
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212
Components on special symmetry positions
IDModelComponents
11A-871-

HOH

21A-955-

HOH

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Components

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


Mass: 32521.135 Da / Num. of mol.: 1 / Mutation: M489A, R492A, E624A, K625A
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
#2: Chemical ChemComp-BNB / N-[2-methyl-3-[4-methyl-6-[4-(4-methylpiperazine-1-carbonyl)anilino]-5-oxo-pyrazin-2-yl]phenyl]-4-(1-piperidyl)benzamide


Mass: 619.756 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C36H41N7O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 189 / 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: 45.81 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8 / Details: 33% PEG3350, 0.1M HEPES

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL9-1 / Wavelength: 0.97946 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: May 2, 2007
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97946 Å / Relative weight: 1
ReflectionResolution: 2→40 Å / Num. obs: 18672 / % possible obs: 92.3 % / Redundancy: 4.2 % / Rmerge(I) obs: 0.104 / Net I/σ(I): 10.1
Reflection shellResolution: 2→2.02 Å / Redundancy: 2.3 % / Rmerge(I) obs: 0.445 / Mean I/σ(I) obs: 1.7 / Num. unique obs: 334 / % possible all: 52.2

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Processing

Software
NameVersionClassification
REFMAC5.2.0019refinement
SCALEPACKdata scaling
DENZOdata reduction
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.01→38.12 Å / Cor.coef. Fo:Fc: 0.946 / Cor.coef. Fo:Fc free: 0.929 / SU B: 10.146 / SU ML: 0.126 / Cross valid method: THROUGHOUT / ESU R: 0.226 / ESU R Free: 0.185
RfactorNum. reflection% reflectionSelection details
Rfree0.23916 949 5.1 %RANDOM
Rwork0.19875 ---
obs0.20083 17688 91.18 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 30.96 Å2
Baniso -1Baniso -2Baniso -3
1-3.02 Å20 Å20 Å2
2---1.34 Å20 Å2
3----1.68 Å2
Refinement stepCycle: 1 / Resolution: 2.01→38.12 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2139 0 46 189 2374
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0222240
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.0411.9843025
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.4015262
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.69824.135104
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.87315401
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.2391512
X-RAY DIFFRACTIONr_chiral_restr0.0680.2316
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.021703
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.1830.2959
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined0.3030.21533
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1320.2126
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1650.244
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.2010.222
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.4841.51367
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it0.7522111
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.07431033
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it1.6894.5914
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.009→2.061 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.364 28 -
Rwork0.253 628 -
obs--44.96 %

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