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- PDB-7n4q: Bruton's tyrosine kinase in complex with compound 45 -

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Basic information

Entry
Database: PDB / ID: 7n4q
TitleBruton's tyrosine kinase in complex with compound 45
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 / regulation of B cell apoptotic process / monocyte proliferation / positive regulation of interleukin-17A production / proteoglycan catabolic process / eosinophil homeostasis / positive regulation of type III hypersensitivity / negative regulation of B cell activation / positive regulation of synoviocyte proliferation / neutrophil homeostasis ...regulation of B cell cytokine production / regulation of B cell apoptotic process / monocyte proliferation / positive regulation of interleukin-17A production / proteoglycan catabolic process / eosinophil homeostasis / positive regulation of type III hypersensitivity / negative regulation of B cell activation / positive regulation of synoviocyte proliferation / neutrophil homeostasis / histamine secretion by mast cell / negative regulation of leukocyte proliferation / positive regulation of type I hypersensitivity / cellular response to molecule of fungal origin / MyD88 deficiency (TLR2/4) / positive regulation of cGAS/STING signaling pathway / IRAK4 deficiency (TLR2/4) / negative regulation of interleukin-10 production / MyD88:MAL(TIRAP) cascade initiated on plasma membrane / positive regulation of B cell differentiation / MyD88-dependent toll-like receptor signaling pathway / phospholipase activator activity / positive regulation of immunoglobulin production / mesoderm development / Fc-epsilon receptor signaling pathway / phosphatidylinositol-3,4,5-trisphosphate binding / B cell activation / positive regulation of NLRP3 inflammasome complex assembly / positive regulation of B cell proliferation / RHO GTPases Activate WASPs and WAVEs / phospholipase binding / peptidyl-tyrosine phosphorylation / FCERI mediated Ca+2 mobilization / B cell receptor signaling pathway / positive regulation of phagocytosis / apoptotic signaling pathway / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / calcium-mediated signaling / non-specific protein-tyrosine kinase / FCGR3A-mediated phagocytosis / cellular response to reactive oxygen species / non-membrane spanning protein tyrosine kinase activity / Regulation of actin dynamics for phagocytic cup formation / positive regulation of interleukin-6 production / T cell receptor signaling pathway / positive regulation of tumor necrosis factor production / adaptive immune response / G beta:gamma signalling through BTK / DAP12 signaling / G alpha (12/13) signalling events / response to lipopolysaccharide / ER-Phagosome pathway / protein tyrosine kinase activity / cytoplasmic vesicle / Potential therapeutics for SARS / G alpha (q) signalling events / positive regulation of canonical NF-kappaB signal transduction / intracellular signal transduction / innate immune response / membrane raft / perinuclear region of cytoplasm / DNA-templated transcription / zinc ion binding / ATP binding / identical protein 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 ...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 / 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-0B9 / Tyrosine-protein kinase BTK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.5 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)31,8712
Polymers31,4281
Non-polymers4431
Water5,026279
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: surface plasmon resonance
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area12570 Å2
MethodPISA
Unit cell
Length a, b, c (Å)72.088, 104.802, 38.183
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-0B9 / (2R)-2-(3-chloro-5-fluoroanilino)-2-cyclopropyl-N-[(3R)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl]acetamide


Mass: 442.917 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H24ClFN6O / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 279 / 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: 2.29 Å3/Da / Density % sol: 46.4 %
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: ROTATING ANODE / Type: RIGAKU FR-D / Wavelength: 1 Å
DetectorType: RIGAKU / Detector: CCD / Date: Sep 25, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.5→50 Å / Num. obs: 42987 / % possible obs: 91.1 % / Redundancy: 4.2 % / Biso Wilson estimate: 22.04 Å2 / Rmerge(I) obs: 0.068 / Net I/σ(I): 38.6
Reflection shellResolution: 1.5→1.55 Å / Rmerge(I) obs: 0.498 / Num. unique obs: 4464

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Processing

Software
NameVersionClassification
PHENIX1.19.1_4122+SVNrefinement
HKL-2000data reduction
HKL-2000data scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3GEN

3gen


Resolution: 1.5→5 Å / SU ML: 0.2272 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 19.5621
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2201 2164 5.04 %
Rwork0.1886 40771 -
obs0.1901 42935 90.95 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 24.59 Å2
Refinement stepCycle: LAST / Resolution: 1.5→5 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2054 0 31 279 2364
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00682192
X-RAY DIFFRACTIONf_angle_d0.96222975
X-RAY DIFFRACTIONf_chiral_restr0.057319
X-RAY DIFFRACTIONf_plane_restr0.0089375
X-RAY DIFFRACTIONf_dihedral_angle_d13.9631816
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.5-1.540.42191650.43572708X-RAY DIFFRACTION92.53
1.54-1.570.34031500.32882851X-RAY DIFFRACTION96.99
1.57-1.620.29531450.23912838X-RAY DIFFRACTION95.95
1.62-1.660.23321480.20072791X-RAY DIFFRACTION94.26
1.66-1.720.24381400.18442816X-RAY DIFFRACTION95.88
1.72-1.780.19811520.19052765X-RAY DIFFRACTION94.01
1.78-1.850.23011590.20072737X-RAY DIFFRACTION92.64
1.85-1.930.24111400.19122691X-RAY DIFFRACTION91.2
1.93-2.040.22221400.17752644X-RAY DIFFRACTION88.63
2.04-2.160.20691340.18582548X-RAY DIFFRACTION85.77
2.16-2.330.21181480.17632513X-RAY DIFFRACTION84.29
2.33-2.560.21841170.18882523X-RAY DIFFRACTION83.6
2.56-2.930.21491570.19192639X-RAY DIFFRACTION87.65
2.94-3.70.21061400.18282820X-RAY DIFFRACTION92.15
3.7-25.430.20221290.16952887X-RAY DIFFRACTION89.36

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