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- PDB-6vxq: Bruton's tyrosine kinase in complex with compound 5 -

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Basic information

Entry
Database: PDB / ID: 6vxq
TitleBruton's tyrosine kinase in complex with compound 5
ComponentsTyrosine-protein kinase BTK
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / kinase / transferase / inhibitor / 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 / 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 / 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 / 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
Chem-RQS / Tyrosine-protein kinase BTK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.4 Å
AuthorsMetrick, C.M. / Marcotte, D.J.
CitationJournal: J.Med.Chem. / Year: 2020
Title: Discovery of BIIB068: A Selective, Potent, Reversible Bruton's Tyrosine Kinase Inhibitor as an Orally Efficacious Agent for Autoimmune Diseases.
Authors: Ma, B. / Bohnert, T. / Otipoby, K.L. / Tien, E. / Arefayene, M. / Bai, J. / Bajrami, B. / Bame, E. / Chan, T.R. / Humora, M. / MacPhee, J.M. / Marcotte, D. / Mehta, D. / Metrick, C.M. / ...Authors: Ma, B. / Bohnert, T. / Otipoby, K.L. / Tien, E. / Arefayene, M. / Bai, J. / Bajrami, B. / Bame, E. / Chan, T.R. / Humora, M. / MacPhee, J.M. / Marcotte, D. / Mehta, D. / Metrick, C.M. / Moniz, G. / Polack, E. / Poreci, U. / Prefontaine, A. / Sheikh, S. / Schroeder, P. / Smirnakis, K. / Zhang, L. / Zheng, F. / Hopkins, B.T.
History
DepositionFeb 23, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 16, 2020Provider: repository / Type: Initial release
Revision 1.1Oct 11, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
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: Tyrosine-protein kinase BTK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,3814
Polymers33,8971
Non-polymers4853
Water4,107228
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)72.433, 104.425, 38.048
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: 33896.859 Da / Num. of mol.: 1
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-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#3: Chemical ChemComp-RQS / N-{[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl]methyl}benzamide


Mass: 328.367 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H16N4O / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 228 / 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: 2.12 Å3/Da / Density % sol: 42.05 %
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: SYNCHROTRON / Site: APS / Beamline: 31-ID / Wavelength: 0.98 Å
DetectorType: RAYONIX MX-225 / Detector: CCD / Date: Mar 6, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 1.31→16.69 Å / Num. obs: 67678 / % possible obs: 97.3 % / Redundancy: 7 % / Biso Wilson estimate: 11.43 Å2 / Rmerge(I) obs: 0.091 / Net I/σ(I): 10.3
Reflection shellResolution: 1.31→1.39 Å / Redundancy: 6.5 % / Rmerge(I) obs: 0.968 / Mean I/σ(I) obs: 2.4 / Num. unique obs: 9185 / % possible all: 92

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Processing

Software
NameVersionClassification
PHENIX1.17.1_3660refinement
HKL-2000data reduction
SCALAdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1K2P

1k2p


Resolution: 1.4→16.69 Å / SU ML: 0.114 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 18.7373
RfactorNum. reflection% reflection
Rfree0.2239 2892 5.12 %
Rwork0.1838 --
obs0.1858 56459 97.83 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 15.63 Å2
Refinement stepCycle: LAST / Resolution: 1.4→16.69 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2072 0 0 228 2300
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00492183
X-RAY DIFFRACTIONf_angle_d0.78372962
X-RAY DIFFRACTIONf_chiral_restr0.0776318
X-RAY DIFFRACTIONf_plane_restr0.0044373
X-RAY DIFFRACTIONf_dihedral_angle_d18.1451322
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.4-1.420.23761460.1812556X-RAY DIFFRACTION100
1.42-1.450.25381480.19842555X-RAY DIFFRACTION99.85
1.45-1.470.27231300.21382594X-RAY DIFFRACTION100
1.47-1.50.24141590.18792530X-RAY DIFFRACTION99.63
1.5-1.530.22611420.16142566X-RAY DIFFRACTION99.96
1.53-1.570.21851280.14952584X-RAY DIFFRACTION100
1.57-1.60.17621440.13742580X-RAY DIFFRACTION100
1.6-1.640.19671520.1362583X-RAY DIFFRACTION100
1.64-1.690.17821560.13432547X-RAY DIFFRACTION100
1.69-1.740.17221310.13582610X-RAY DIFFRACTION100
1.74-1.790.20011270.14242583X-RAY DIFFRACTION100
1.79-1.860.1751190.15662611X-RAY DIFFRACTION100
1.86-1.930.34661140.29352245X-RAY DIFFRACTION86.47
1.93-2.020.26751360.2052553X-RAY DIFFRACTION97.53
2.02-2.120.1971550.17422586X-RAY DIFFRACTION100
2.12-2.260.30011330.25622346X-RAY DIFFRACTION89.69
2.26-2.430.21091340.18742297X-RAY DIFFRACTION88.53
2.43-2.670.20041560.1812628X-RAY DIFFRACTION100
2.68-3.060.2159960.18722687X-RAY DIFFRACTION100
3.06-3.850.23051370.18062613X-RAY DIFFRACTION96.53
3.85-16.690.19391490.16712713X-RAY DIFFRACTION96.62

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