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- PDB-8flv: Bruton's tyrosine kinase in complex with compound 34 -

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Basic information

Entry
Database: PDB / ID: 8flv
TitleBruton's tyrosine kinase in complex with compound 34
ComponentsTyrosine-protein kinase BTK
KeywordsTRANSFERASE/INHIBITOR / tyrosine protein kinase BTK / LIGASE / 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 / positive regulation of synoviocyte proliferation / histamine secretion by mast cell ...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 / positive regulation of synoviocyte proliferation / histamine secretion by mast cell / 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) / positive regulation of immunoglobulin production / 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 / mesoderm development / phosphatidylinositol-3,4,5-trisphosphate binding / phospholipase binding / 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 / calcium-mediated signaling / apoptotic signaling pathway / FCGR3A-mediated phagocytosis / B cell receptor signaling pathway / non-specific protein-tyrosine kinase / non-membrane spanning protein tyrosine kinase activity / Regulation of actin dynamics for phagocytic cup formation / G beta:gamma signalling through BTK / cellular response to reactive oxygen species / peptidyl-tyrosine phosphorylation / positive regulation of interleukin-6 production / positive regulation of tumor necrosis factor production / G alpha (12/13) signalling events / DAP12 signaling / positive regulation of NF-kappaB transcription factor activity / T cell receptor signaling pathway / ER-Phagosome pathway / cytoplasmic vesicle / G alpha (q) signalling events / protein tyrosine kinase activity / adaptive immune response / Potential therapeutics for SARS / response to lipopolysaccharide / intracellular signal transduction / membrane raft / protein phosphorylation / innate immune response / perinuclear region of cytoplasm / ATP binding / identical protein binding / nucleus / metal ion binding / 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 / 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 / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
DI(HYDROXYETHYL)ETHER / Chem-ZB9 / Tyrosine-protein kinase BTK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.3 Å
AuthorsMetrick, C.M. / Marcotte, D.J.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2023
Title: Discovery of structural diverse reversible BTK inhibitors utilized to develop a novel in vivo CD69 and CD86 PK/PD mouse model.
Authors: Vandeveer, G.H. / Arduini, R.M. / Baker, D.P. / Barry, K. / Bohnert, T. / Bowden-Verhoek, J.K. / Conlon, P. / Cullen, P.F. / Guan, B. / Jenkins, T.J. / Liao, S.Y. / Lin, L. / Liu, Y.T. / ...Authors: Vandeveer, G.H. / Arduini, R.M. / Baker, D.P. / Barry, K. / Bohnert, T. / Bowden-Verhoek, J.K. / Conlon, P. / Cullen, P.F. / Guan, B. / Jenkins, T.J. / Liao, S.Y. / Lin, L. / Liu, Y.T. / Marcotte, D. / Mertsching, E. / Metrick, C.M. / Negrou, E. / Powell, N. / Scott, D. / Silvian, L.F. / Hopkins, B.T.
History
DepositionDec 22, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 5, 2023Provider: repository / Type: Initial release
Revision 1.1May 22, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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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)33,4546
Polymers32,6801
Non-polymers7745
Water4,396244
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: surface plasmon resonance
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)71.444, 104.846, 37.964
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21212
Space group name HallP22ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x+1/2,y+1/2,-z
#4: -x,-y,z

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Components

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


Mass: 32680.471 Da / Num. of mol.: 1 / Fragment: Protein kinase domain residues 382-659
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-ZB9 / 2-(3,5-dichloroanilino)-1-{(3R)-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl}ethan-1-one


Mass: 433.334 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H22Cl2N6O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 244 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 46.01 %
Crystal growTemperature: 277 K / Method: vapor diffusion / Details: bis-tris, ammonium salt, PEG

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E+ SUPERBRIGHT / Wavelength: 1.54 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Aug 9, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 1.3→50 Å / Num. obs: 58604 / % possible obs: 80.6 % / Redundancy: 5.4 % / Biso Wilson estimate: 12.97 Å2 / Rmerge(I) obs: 0.123 / Net I/σ(I): 6.2
Reflection shellResolution: 1.3→1.36 Å / Rmerge(I) obs: 1.687 / Num. unique obs: 2179

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Processing

SoftwareName: PHENIX / Version: 1.20.1_4487 / Classification: refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.3→29.52 Å / SU ML: 0.1538 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 24.2296
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2181 2965 5.13 %
Rwork0.1941 54810 -
obs0.1954 57775 80.6 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 17.64 Å2
Refinement stepCycle: LAST / Resolution: 1.3→29.52 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2116 0 48 244 2408
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00672292
X-RAY DIFFRACTIONf_angle_d0.91023108
X-RAY DIFFRACTIONf_chiral_restr0.0891329
X-RAY DIFFRACTIONf_plane_restr0.009394
X-RAY DIFFRACTIONf_dihedral_angle_d14.1196851
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.3-1.320.68660.6268128X-RAY DIFFRACTION4.03
1.32-1.340.5501230.498448X-RAY DIFFRACTION14.2
1.34-1.360.449570.41641109X-RAY DIFFRACTION34.26
1.36-1.390.4302920.38641548X-RAY DIFFRACTION48.91
1.39-1.420.3274990.35041952X-RAY DIFFRACTION60.34
1.42-1.450.3731260.32972295X-RAY DIFFRACTION71.93
1.45-1.480.37371280.31132519X-RAY DIFFRACTION79.2
1.48-1.520.30661640.27822810X-RAY DIFFRACTION86.76
1.52-1.560.30361690.26362945X-RAY DIFFRACTION92.87
1.56-1.610.24821660.24473165X-RAY DIFFRACTION98.46
1.61-1.660.24011760.22143223X-RAY DIFFRACTION99.62
1.66-1.720.24341700.20773213X-RAY DIFFRACTION99.47
1.72-1.790.22641570.20283195X-RAY DIFFRACTION99.5
1.79-1.870.23441620.19263227X-RAY DIFFRACTION99.38
1.87-1.970.22271680.17573212X-RAY DIFFRACTION99.59
1.97-2.090.18781670.16733256X-RAY DIFFRACTION99.77
2.09-2.250.17961880.16323235X-RAY DIFFRACTION99.83
2.25-2.480.20641760.1713273X-RAY DIFFRACTION100
2.48-2.840.20071850.17753284X-RAY DIFFRACTION100
2.84-3.570.20692050.17533307X-RAY DIFFRACTION100
3.57-29.520.1751810.16763466X-RAY DIFFRACTION99.16

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