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- PDB-3ocs: Crystal structure of bruton's tyrosine kinase in complex with inh... -

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Basic information

Entry
Database: PDB / ID: 3ocs
TitleCrystal structure of bruton's tyrosine kinase in complex with inhibitor CGI1746
ComponentsTyrosine-protein kinase BTK
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / Tyrosine kinase / TRANSFERASE / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


regulation of B cell cytokine production / monocyte proliferation / positive regulation of interleukin-17A production / eosinophil homeostasis / regulation of B cell apoptotic process / proteoglycan catabolic 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 / monocyte proliferation / positive regulation of interleukin-17A production / eosinophil homeostasis / regulation of B cell apoptotic process / proteoglycan catabolic 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 / MyD88 deficiency (TLR2/4) / cellular response to interleukin-7 / 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 / B cell activation / phosphatidylinositol-3,4,5-trisphosphate binding / RHO GTPases Activate WASPs and WAVEs / phospholipase binding / 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 / B cell receptor signaling pathway / FCGR3A-mediated phagocytosis / non-membrane spanning protein tyrosine kinase activity / non-specific protein-tyrosine kinase / apoptotic signaling pathway / peptidyl-tyrosine phosphorylation / calcium-mediated signaling / positive regulation of NF-kappaB transcription factor activity / Regulation of actin dynamics for phagocytic cup formation / positive regulation of interleukin-6 production / G beta:gamma signalling through BTK / positive regulation of tumor necrosis factor production / DAP12 signaling / G alpha (12/13) signalling events / T cell receptor signaling pathway / ER-Phagosome pathway / cytoplasmic vesicle / protein tyrosine kinase activity / response to lipopolysaccharide / G alpha (q) signalling events / adaptive immune response / 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 / 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 / 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-746 / BETA-MERCAPTOETHANOL / Tyrosine-protein kinase BTK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsDavies, D.R. / Gallion, S.L. / Staker, B.L.
CitationJournal: To be Published
Title: A novel, specific Btk inhibitor antagonizes BCR and Fc[gamma]R signaling and suppresses inflammatory arthritis
Authors: Di Paolo, J.A. / Huang, T. / Balazs, M. / Barbosa, J. / Barck, K.H. / Carano, R.A.D. / Darrow, J. / Davies, D.R. / DeForge, L.E. / Dennis Jr., G. / Diehl, L. / Ferrando, R.
History
DepositionAug 10, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 3, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Sep 6, 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_conn / 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_conn.pdbx_leaving_atom_flag / _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

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Assembly

Deposited unit
A: Tyrosine-protein kinase BTK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,6446
Polymers31,6981
Non-polymers9465
Water2,864159
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)108.386, 108.386, 41.974
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number169
Space group name H-MP61

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Components

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


Mass: 31698.471 Da / Num. of mol.: 1 / Fragment: RESIDUES 393-656
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BTK, AGMX1, ATK, BPK / Plasmid: PBACGUS / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q06187, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-BME / BETA-MERCAPTOETHANOL


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS
#4: Chemical ChemComp-746 / 4-tert-butyl-N-[2-methyl-3-(4-methyl-6-{[4-(morpholin-4-ylcarbonyl)phenyl]amino}-5-oxo-4,5-dihydropyrazin-2-yl)phenyl]benzamide / CGI1746


Mass: 579.689 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C34H37N5O4
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 159 / 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: 2.25 Å3/Da / Density % sol: 45.22 %
Crystal growTemperature: 289 K / Method: vapor diffusion, sitting drop / pH: 7
Details: 14% PEG 10,000, 150 MM LI2SO4, 100 MM IMIDAZOLE, PH 7.0, 0.75% OCTYL-B-D-GLUCOPYRANOSIDE, VAPOR DIFFUSION, TEMPERATURE 289K, VAPOR DIFFUSION, SITTING DROP

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL1-5 / Wavelength: 0.97944 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Feb 1, 2006
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97944 Å / Relative weight: 1
ReflectionResolution: 1.8→94.07 Å / Num. obs: 26112 / % possible obs: 99 % / Redundancy: 4.7 % / Rmerge(I) obs: 0.072 / Net I/σ(I): 9.1
Reflection shellResolution: 1.8→1.86 Å / Redundancy: 2.9 % / Rmerge(I) obs: 0.501 / % possible all: 91.1

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Processing

Software
NameVersionClassification
MOLREPphasing
REFMAC5.2.0005refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1K2P

1k2p


Resolution: 1.8→94.07 Å / Cor.coef. Fo:Fc: 0.956 / Cor.coef. Fo:Fc free: 0.948 / SU B: 2.488 / SU ML: 0.078 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.12 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.213 1323 5.1 %RANDOM
Rwork0.183 ---
obs0.184 26079 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 20.75 Å2
Baniso -1Baniso -2Baniso -3
1-0.52 Å20.26 Å20 Å2
2--0.52 Å20 Å2
3----0.78 Å2
Refinement stepCycle: LAST / Resolution: 1.8→94.07 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2100 0 62 159 2321
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0222212
X-RAY DIFFRACTIONr_angle_refined_deg1.4941.9842996
X-RAY DIFFRACTIONr_dihedral_angle_1_deg10.6215263
X-RAY DIFFRACTIONr_dihedral_angle_2_deg29.72923.9898
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.24515370
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.7821511
X-RAY DIFFRACTIONr_chiral_restr0.1140.2318
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.021667
X-RAY DIFFRACTIONr_nbd_refined0.2010.21044
X-RAY DIFFRACTIONr_nbtor_refined0.3120.21518
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1420.2170
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1970.249
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.2180.215
X-RAY DIFFRACTIONr_mcbond_it0.9651.51349
X-RAY DIFFRACTIONr_mcangle_it1.42622106
X-RAY DIFFRACTIONr_scbond_it2.36831011
X-RAY DIFFRACTIONr_scangle_it3.4954.5890
LS refinement shellResolution: 1.8→1.85 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.335 85 -
Rwork0.268 1627 -
obs--88.75 %

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