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- PDB-7n4r: Bruton's tyrosine kinase in complex with compound 21 -

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Basic information

Entry
Database: PDB / ID: 7n4r
TitleBruton's tyrosine kinase in complex with compound 21
ComponentsTyrosine-protein kinase BTK
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / transferase / transferase inhibitor / kinase / kinase 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 / 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 B cell proliferation / positive regulation of phagocytosis / 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
Chem-0BG / Tyrosine-protein kinase BTK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.62 Å
AuthorsMetrick, C.M. / Marcotte, D.J.
CitationJournal: Bioorg.Med.Chem. / Year: 2021
Title: Utilizing structure based drug design and metabolic soft spot identification to optimize the in vitro potency and in vivo pharmacokinetic properties leading to the discovery of novel ...Title: Utilizing structure based drug design and metabolic soft spot identification to optimize the in vitro potency and in vivo pharmacokinetic properties leading to the discovery of novel reversible Bruton's tyrosine kinase inhibitors.
Authors: Hopkins, B.T. / Bame, E. / Bell, N. / Bohnert, T. / Bowden-Verhoek, J.K. / Bui, M. / Cancilla, M.T. / Conlon, P. / Cullen, P. / Erlanson, D.A. / Fan, J. / Fuchs-Knotts, T. / Hansen, S. / ...Authors: Hopkins, B.T. / Bame, E. / Bell, N. / Bohnert, T. / Bowden-Verhoek, J.K. / Bui, M. / Cancilla, M.T. / Conlon, P. / Cullen, P. / Erlanson, D.A. / Fan, J. / Fuchs-Knotts, T. / Hansen, S. / Heumann, S. / Jenkins, T.J. / Gua, C. / Liu, Y. / Liu, Y. / Lulla, M. / Marcotte, D. / Marx, I. / McDowell, B. / Mertsching, E. / Negrou, E. / Romanowski, M.J. / Scott, D. / Silvian, L. / Yang, W. / Zhong, M.
History
DepositionJun 4, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 18, 2022Provider: repository / Type: Initial release
Revision 1.1Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)31,8313
Polymers31,4281
Non-polymers4032
Water3,387188
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: surface plasmon resonance
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)71.800, 104.691, 38.053
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: 31428.078 Da / Num. of mol.: 1 / Fragment: KINASE DOMAIN
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-0BG / N-{2-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]ethyl}-N~2~-phenylglycinamide


Mass: 324.380 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H20N6O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 188 / 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: 45.94 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop
Details: 0.1M BisTRIS pH 6.5, 0.2M Ammonium Acetate, 0.1M Guanidine HCl, 20% PEG2200 MME

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 31-ID / Wavelength: 1 Å
DetectorType: RAYONIX MX-225 / Detector: CCD / Date: Mar 27, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.62→21.76 Å / Num. obs: 36187 / % possible obs: 96.6 % / Redundancy: 4.5 % / Biso Wilson estimate: 16.57 Å2 / Rmerge(I) obs: 0.136 / Net I/σ(I): 8.9
Reflection shellResolution: 1.62→1.71 Å / Rmerge(I) obs: 0.461 / Num. unique obs: 44630

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Processing

Software
NameVersionClassification
PHENIX1.19.1_4122+SVNphasing
PHENIX1.19.1_4122+SVNrefinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5p9j

5p9j


Resolution: 1.62→21.56 Å / SU ML: 0.1806 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 22.0965
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2221 1784 4.99 %
Rwork0.1921 33990 -
obs0.1936 35774 96.69 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 19.92 Å2
Refinement stepCycle: LAST / Resolution: 1.62→21.56 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2041 0 28 188 2257
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0162178
X-RAY DIFFRACTIONf_angle_d1.4732950
X-RAY DIFFRACTIONf_chiral_restr0.0889314
X-RAY DIFFRACTIONf_plane_restr0.0145374
X-RAY DIFFRACTIONf_dihedral_angle_d14.4137811
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.62-1.670.29631150.23362263X-RAY DIFFRACTION84.75
1.67-1.720.22941130.21472541X-RAY DIFFRACTION94.65
1.72-1.770.27231370.20212530X-RAY DIFFRACTION95.35
1.77-1.840.2141510.18852585X-RAY DIFFRACTION97.89
1.84-1.910.27641290.23942582X-RAY DIFFRACTION96.65
1.91-20.29781300.23712539X-RAY DIFFRACTION94.51
2-2.10.271260.21652595X-RAY DIFFRACTION96.32
2.1-2.230.20581410.17592673X-RAY DIFFRACTION99.58
2.23-2.410.21491490.18192646X-RAY DIFFRACTION98.69
2.41-2.650.18581410.18792712X-RAY DIFFRACTION99.86
2.65-3.030.22711520.1992702X-RAY DIFFRACTION99.62
3.03-3.810.19551420.18292750X-RAY DIFFRACTION99.25
3.81-21.560.2111580.16882872X-RAY DIFFRACTION99.38

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