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- PDB-5kup: Bruton's tyrosine kinase (BTK) with pyridazinone compound 9 -

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Basic information

Entry
Database: PDB / ID: 5kup
TitleBruton's tyrosine kinase (BTK) with pyridazinone compound 9
ComponentsTyrosine-protein kinase BTK
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / protein kinase / inhibitor / non covalent / 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 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; 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-6XL / Tyrosine-protein kinase BTK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.389 Å
AuthorsEigenbrot, C. / Yu, C.
CitationJournal: Acs Chem.Biol. / Year: 2016
Title: Battling Btk Mutants With Noncovalent Inhibitors That Overcome Cys481 and Thr474 Mutations.
Authors: Johnson, A.R. / Kohli, P.B. / Katewa, A. / Gogol, E. / Belmont, L.D. / Choy, R. / Penuel, E. / Burton, L. / Eigenbrot, C. / Yu, C. / Ortwine, D.F. / Bowman, K. / Franke, Y. / Tam, C. / ...Authors: Johnson, A.R. / Kohli, P.B. / Katewa, A. / Gogol, E. / Belmont, L.D. / Choy, R. / Penuel, E. / Burton, L. / Eigenbrot, C. / Yu, C. / Ortwine, D.F. / Bowman, K. / Franke, Y. / Tam, C. / Estevez, A. / Mortara, K. / Wu, J. / Li, H. / Lin, M. / Bergeron, P. / Crawford, J.J. / Young, W.B.
History
DepositionJul 13, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 14, 2016Provider: repository / Type: Initial release
Revision 1.1Nov 2, 2016Group: Database references
Revision 1.2Oct 4, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_struct_oper_list
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_oper_list.symmetry_operation

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Tyrosine-protein kinase BTK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,8137
Polymers31,7891
Non-polymers1,0246
Water5,747319
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1100 Å2
ΔGint-21 kcal/mol
Surface area13080 Å2
MethodPISA
Unit cell
Length a, b, c (Å)108.373, 108.373, 42.453
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number169
Space group name H-MP61

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Components

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Protein , 1 types, 1 molecules A

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


Mass: 31788.592 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

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Non-polymers , 5 types, 325 molecules

#2: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical ChemComp-PG0 / 2-(2-METHOXYETHOXY)ETHANOL / PEG 6000 / 2-(2-Methoxyethoxy)ethanol


Mass: 120.147 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C5H12O3 / Comment: inhibitor, precipitant*YM
#5: Chemical ChemComp-6XL / 6-~{tert}-butyl-8-fluoranyl-2-[3-(hydroxymethyl)-4-[1-methyl-6-oxidanylidene-5-(pyrimidin-4-ylamino)pyridin-3-yl]pyridin-2-yl]phthalazin-1-one


Mass: 527.550 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H26FN7O3
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 319 / Source method: isolated from a natural source / Formula: H2O

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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: 2.26 Å3/Da / Density % sol: 45.67 %
Crystal growTemperature: 286 K / Method: vapor diffusion, hanging drop / pH: 5.5 / Details: PEG 10K, citrate, LiSO4

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Data collection

DiffractionMean temperature: 110 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-F / Wavelength: 0.9787 Å
DetectorType: RAYONIX MX-225 / Detector: CCD / Date: Jun 5, 2014
RadiationMonochromator: diamond (111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9787 Å / Relative weight: 1
ReflectionResolution: 1.389→35.5 Å / Num. obs: 56763 / % possible obs: 98.5 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 8.2 % / Biso Wilson estimate: 14.4 Å2 / Rsym value: 0.075 / Net I/σ(I): 28
Reflection shellResolution: 1.39→1.44 Å / Redundancy: 7.7 % / Rmerge(I) obs: 0.897 / Mean I/σ(I) obs: 2.6 / % possible all: 97

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
HKL-2000data reduction
SCALEPACKdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3OCS

3ocs


Resolution: 1.389→35.473 Å / SU ML: 0.12 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 17.62
RfactorNum. reflection% reflectionSelection details
Rfree0.1772 2919 5.14 %random
Rwork0.1655 ---
obs0.1661 56761 98.47 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Refinement stepCycle: LAST / Resolution: 1.389→35.473 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2175 0 69 319 2563
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0062402
X-RAY DIFFRACTIONf_angle_d1.1693260
X-RAY DIFFRACTIONf_dihedral_angle_d12.824927
X-RAY DIFFRACTIONf_chiral_restr0.083336
X-RAY DIFFRACTIONf_plane_restr0.005414
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.3887-1.41150.28151620.24372466X-RAY DIFFRACTION97
1.4115-1.43580.20271410.23312498X-RAY DIFFRACTION97
1.4358-1.46190.22251160.21212531X-RAY DIFFRACTION97
1.4619-1.49010.22681340.20222522X-RAY DIFFRACTION98
1.4901-1.52050.20581420.19872508X-RAY DIFFRACTION97
1.5205-1.55350.2241340.19432539X-RAY DIFFRACTION98
1.5535-1.58970.19231250.17982557X-RAY DIFFRACTION98
1.5897-1.62940.19871350.17192509X-RAY DIFFRACTION97
1.6294-1.67350.19051520.17582554X-RAY DIFFRACTION99
1.6735-1.72270.19131390.1622560X-RAY DIFFRACTION98
1.7227-1.77830.18641340.16382547X-RAY DIFFRACTION98
1.7783-1.84190.1671490.16442543X-RAY DIFFRACTION99
1.8419-1.91560.20181320.16332597X-RAY DIFFRACTION99
1.9156-2.00280.16331590.15512563X-RAY DIFFRACTION99
2.0028-2.10840.17071230.15762593X-RAY DIFFRACTION99
2.1084-2.24050.17921510.15652576X-RAY DIFFRACTION99
2.2405-2.41340.19831280.1672603X-RAY DIFFRACTION100
2.4134-2.65620.1731280.16892622X-RAY DIFFRACTION100
2.6562-3.04040.17231560.16332603X-RAY DIFFRACTION100
3.0404-3.82990.16541480.14762638X-RAY DIFFRACTION100
3.8299-35.4850.14951310.16082713X-RAY DIFFRACTION100

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