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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 / proteoglycan catabolic process / monocyte proliferation / positive regulation of interleukin-17A production / eosinophil homeostasis / regulation of B cell apoptotic 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 / proteoglycan catabolic process / monocyte proliferation / positive regulation of interleukin-17A production / eosinophil homeostasis / regulation of B cell apoptotic 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 / cellular response to interleukin-7 / MyD88 deficiency (TLR2/4) / 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 / phospholipase binding / phosphatidylinositol-3,4,5-trisphosphate binding / B cell activation / RHO GTPases Activate WASPs and WAVEs / cell maturation / positive regulation of phagocytosis / positive regulation of B cell proliferation / FCERI mediated Ca+2 mobilization / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / cellular response to reactive oxygen species / non-membrane spanning protein tyrosine kinase activity / B cell receptor signaling pathway / FCGR3A-mediated phagocytosis / non-specific protein-tyrosine kinase / apoptotic signaling pathway / calcium-mediated signaling / peptidyl-tyrosine phosphorylation / Regulation of actin dynamics for phagocytic cup formation / positive regulation of interleukin-6 production / G beta:gamma signalling through BTK / positive regulation of NF-kappaB transcription factor activity / positive regulation of tumor necrosis factor production / DAP12 signaling / G alpha (12/13) signalling events / T cell receptor signaling pathway / ER-Phagosome pathway / protein tyrosine kinase activity / cytoplasmic vesicle / G alpha (q) signalling events / adaptive immune response / response to lipopolysaccharide / Potential therapeutics for SARS / intracellular signal transduction / protein phosphorylation / membrane raft / innate immune response / perinuclear region of cytoplasm / 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 / SH2 domain superfamily / Src homology 3 domains / 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. / Tyrosine-protein kinase, active site / PH-like domain superfamily / 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-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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