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- PDB-4rx5: Bruton's tyrosine kinase (BTK) with pyridazinone compound 23 -

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Basic information

Entry
Database: PDB / ID: 4rx5
TitleBruton's tyrosine kinase (BTK) with pyridazinone compound 23
ComponentsTyrosine-protein kinase BTK
KeywordsTRANSFERASE / protein kinase / phosphotransfer catalyst
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-3YO / Tyrosine-protein kinase BTK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.356 Å
AuthorsEigenbrot, C. / Yu, C.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2016
Title: Discovery of highly potent and selective Bruton's tyrosine kinase inhibitors: Pyridazinone analogs with improved metabolic stability.
Authors: Young, W.B. / Barbosa, J. / Blomgren, P. / Bremer, M.C. / Crawford, J.J. / Dambach, D. / Eigenbrot, C. / Gallion, S. / Johnson, A.R. / Kropf, J.E. / Lee, S.H. / Liu, L. / Lubach, J.W. / ...Authors: Young, W.B. / Barbosa, J. / Blomgren, P. / Bremer, M.C. / Crawford, J.J. / Dambach, D. / Eigenbrot, C. / Gallion, S. / Johnson, A.R. / Kropf, J.E. / Lee, S.H. / Liu, L. / Lubach, J.W. / Macaluso, J. / Maciejewski, P. / Mitchell, S.A. / Ortwine, D.F. / Di Paolo, J. / Reif, K. / Scheerens, H. / Schmitt, A. / Wang, X. / Wong, H. / Xiong, J.M. / Xu, J. / Yu, C. / Zhao, Z. / Currie, K.S.
History
DepositionDec 8, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 2, 2015Provider: repository / Type: Initial release
Revision 1.1Mar 23, 2016Group: Database references
Revision 1.2Sep 20, 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 / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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)32,8157
Polymers31,7891
Non-polymers1,0266
Water5,729318
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)108.300, 108.300, 42.422
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 / Fragment: kinase domain (UNP residues 393-657)
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, 324 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-3YO / N-(6-fluoro-2-methyl-3-{5-[(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)amino]-6-oxo-1,6-dihydropyridazin-3-yl}phenyl)-1-benzothiophene-2-carboxamide


Mass: 529.589 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H24FN7O2S
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 318 / 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: 45.56 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7
Details: PEG 10000, Li2SO4, pH 7.0, VAPOR DIFFUSION, SITTING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 110 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-2 / Wavelength: 0.9795 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 19, 2014
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 1.356→38.65 Å / Num. all: 61812 / Num. obs: 61256 / % possible obs: 99.1 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 9.7 % / Biso Wilson estimate: 16.3 Å2 / Rsym value: 0.44 / Net I/σ(I): 26.1

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Processing

Software
NameVersionClassification
Blu-Icedata collection
PHASERphasing
PHENIX(phenix.refine: 1.9_1692)refinement
XDSdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3P08

3p08


Resolution: 1.356→38.65 Å / SU ML: 0.13 / σ(F): 1.89 / Phase error: 17.5 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.1786 3161 5.16 %random
Rwork0.16 ---
obs0.1609 61256 99.15 %-
all-61812 --
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refine analyzeLuzzati sigma a obs: 0.13 Å
Refinement stepCycle: LAST / Resolution: 1.356→38.65 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2175 0 68 318 2561
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0052386
X-RAY DIFFRACTIONf_angle_d1.0643235
X-RAY DIFFRACTIONf_dihedral_angle_d12.276916
X-RAY DIFFRACTIONf_chiral_restr0.079335
X-RAY DIFFRACTIONf_plane_restr0.004409
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.356-1.37630.29861160.27422049X-RAY DIFFRACTION81
1.3763-1.39780.25141420.22962529X-RAY DIFFRACTION100
1.3978-1.42070.23891730.2152486X-RAY DIFFRACTION100
1.4207-1.44520.1881250.20092534X-RAY DIFFRACTION100
1.4452-1.47150.22491350.19492557X-RAY DIFFRACTION100
1.4715-1.49980.22171370.18792517X-RAY DIFFRACTION100
1.4998-1.53040.18331400.1832525X-RAY DIFFRACTION100
1.5304-1.56370.19631270.182556X-RAY DIFFRACTION100
1.5637-1.60010.21441200.16772535X-RAY DIFFRACTION100
1.6001-1.64010.18411380.16592555X-RAY DIFFRACTION100
1.6401-1.68440.19481570.16512505X-RAY DIFFRACTION100
1.6844-1.7340.19591400.16422521X-RAY DIFFRACTION100
1.734-1.78990.16851340.15542554X-RAY DIFFRACTION100
1.7899-1.85390.17631370.162521X-RAY DIFFRACTION100
1.8539-1.92810.19671380.15822567X-RAY DIFFRACTION100
1.9281-2.01590.1681580.15692518X-RAY DIFFRACTION100
2.0159-2.12220.191270.15272579X-RAY DIFFRACTION100
2.1222-2.25510.15781340.15192542X-RAY DIFFRACTION100
2.2551-2.42920.19511310.15792561X-RAY DIFFRACTION100
2.4292-2.67360.19221300.16682558X-RAY DIFFRACTION100
2.6736-3.06040.18071500.16182572X-RAY DIFFRACTION100
3.0604-3.85520.1681420.14292588X-RAY DIFFRACTION100
3.8552-38.66780.14581300.15052666X-RAY DIFFRACTION100

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