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- PDB-4otq: Crystal structure of BTK kinase domain complexed with 1-[5-[3-(7-... -

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Basic information

Entry
Database: PDB / ID: 4otq
TitleCrystal structure of BTK kinase domain complexed with 1-[5-[3-(7-tert-butyl-4-oxo-quinazolin-3-yl)-2-methyl-phenyl]-1-methyl-2-oxo-3-pyridyl]-3-methyl-urea
ComponentsTyrosine-protein kinase BTK
KeywordsTRANSFERASE/TRANSFERASE 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 / eosinophil homeostasis / 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 / regulation of B cell apoptotic process / monocyte proliferation / positive regulation of interleukin-17A production / eosinophil homeostasis / 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 / phosphatidylinositol-3,4,5-trisphosphate binding / B cell activation / RHO GTPases Activate WASPs and WAVEs / phospholipase binding / cell maturation / positive regulation of B cell proliferation / FCERI mediated Ca+2 mobilization / positive regulation of phagocytosis / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / peptidyl-tyrosine phosphorylation / cellular response to reactive oxygen species / B cell receptor signaling pathway / non-membrane spanning protein tyrosine kinase activity / FCGR3A-mediated phagocytosis / non-specific protein-tyrosine kinase / apoptotic signaling pathway / 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 / Potential therapeutics for SARS / adaptive immune response / positive regulation of canonical NF-kappaB signal transduction / intracellular signal transduction / membrane raft / innate immune response / perinuclear region of cytoplasm / zinc ion binding / ATP binding / identical protein binding / nucleus / plasma membrane / cytoplasm / cytosol
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-2V2 / Tyrosine-protein kinase BTK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.55 Å
AuthorsKuglstatter, A. / Wong, A.
CitationJournal: J.Med.Chem. / Year: 2015
Title: Structure-Based Drug Design of RN486, a Potent and Selective Bruton's Tyrosine Kinase (BTK) Inhibitor, for the Treatment of Rheumatoid Arthritis.
Authors: Lou, Y. / Han, X. / Kuglstatter, A. / Kondru, R.K. / Sweeney, Z.K. / Soth, M. / McIntosh, J. / Litman, R. / Suh, J. / Kocer, B. / Davis, D. / Park, J. / Frauchiger, S. / Dewdney, N. / Zecic, ...Authors: Lou, Y. / Han, X. / Kuglstatter, A. / Kondru, R.K. / Sweeney, Z.K. / Soth, M. / McIntosh, J. / Litman, R. / Suh, J. / Kocer, B. / Davis, D. / Park, J. / Frauchiger, S. / Dewdney, N. / Zecic, H. / Taygerly, J.P. / Sarma, K. / Hong, J. / Hill, R.J. / Gabriel, T. / Goldstein, D.M. / Owens, T.D.
History
DepositionFeb 14, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 14, 2014Provider: repository / Type: Initial release
Revision 1.1Jan 21, 2015Group: Database references
Revision 1.2Jul 17, 2019Group: Data collection / Refinement description / Category: software
Item: _software.classification / _software.name / _software.version
Revision 1.3Sep 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)33,1494
Polymers32,5211
Non-polymers6283
Water4,666259
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)71.886, 106.562, 38.304
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212

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Components

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


Mass: 32521.135 Da / Num. of mol.: 1 / Fragment: UNP residues 378-659 / Mutation: M489A, R492A, E624A, K625A
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-2V2 / 1-{5-[3-(7-tert-butyl-4-oxoquinazolin-3(4H)-yl)-2-methylphenyl]-1-methyl-2-oxo-1,2-dihydropyridin-3-yl}-3-methylurea


Mass: 471.551 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H29N5O3
#3: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 259 / 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: 45.47 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8
Details: 33% PEG3350, 0.1 M HEPES, pH 8.0, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL9-2 / Wavelength: 0.97946 Å
DetectorType: MARMOSAIC 325 mm CCD / Detector: CCD
RadiationMonochromator: Double crystal Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97946 Å / Relative weight: 1
ReflectionResolution: 1.55→42.8 Å / Num. obs: 43604 / % possible obs: 99.5 % / Redundancy: 4.7 % / Biso Wilson estimate: 21.7 Å2 / Rsym value: 0.067 / Net I/σ(I): 17.6
Reflection shellResolution: 1.55→1.59 Å / Redundancy: 4.1 % / Mean I/σ(I) obs: 2.3 / Num. unique all: 2667 / Rsym value: 0.413 / % possible all: 99.64

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Processing

Software
NameVersionClassification
REFMAC5.8.0048refinement
CNSrefinement
ADSCQuantumdata collection
DENZOdata reduction
SCALEPACKdata scaling
CNSphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: PDB ENTRY 3PIX

3pix


Resolution: 1.55→42.8 Å / Cor.coef. Fo:Fc: 0.973 / Cor.coef. Fo:Fc free: 0.961 / SU B: 3.169 / SU ML: 0.051 / Cross valid method: THROUGHOUT / ESU R: 0.083 / ESU R Free: 0.073 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.18882 2191 5 %RANDOM
Rwork0.14808 ---
obs0.15022 41259 99.64 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 25.359 Å2
Baniso -1Baniso -2Baniso -3
1--0.06 Å2-0 Å2-0 Å2
2--0.63 Å2-0 Å2
3----0.57 Å2
Refinement stepCycle: LAST / Resolution: 1.55→42.8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2139 0 43 259 2441
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.020.0192233
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.7281.9813016
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.8365262
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.28924.135104
X-RAY DIFFRACTIONr_dihedral_angle_3_deg10.98415401
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.4791512
X-RAY DIFFRACTIONr_chiral_restr0.1480.2318
X-RAY DIFFRACTIONr_gen_planes_refined0.0110.0211711
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.4961.7061051
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it2.8462.5611312
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it3.6372.031182
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined4.4816.4763749
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr7.01532233
X-RAY DIFFRACTIONr_sphericity_free22.269585
X-RAY DIFFRACTIONr_sphericity_bonded10.6952357
LS refinement shellResolution: 1.55→1.59 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.303 157 -
Rwork0.218 2904 -
obs--96.56 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.03860.12070.1073.0121-0.00740.40120.01730.0078-0.0411-0.05150.09410.04910.09770.0219-0.11140.082-0.0040.00430.0079-0.00330.065319.0551-1.91837.6958
20.39880.0123-0.18440.3224-0.09260.91560.0041-0.00090.0524-0.0020.02120.0155-0.0473-0.0195-0.02530.0479-0.0004-0.00170.0120.00040.007618.99827.23982.7118
36.8009-0.46772.7341.2398-2.10944.2862-0.0144-0.0455-0.56120.060.24020.04990.0192-0.3917-0.22580.11250.01190.01630.0460.0060.048316.22095.174419.6175
41.74561.70743.2322.40432.78916.34170.02260.2659-0.17390.06510.1917-0.25340.15410.6099-0.21420.10750.05040.04780.10230.01190.056228.82274.3627.2417
50.4465-0.06860.22650.5392-0.37131.4864-0.0164-0.0532-0.0227-0.00780.0048-0.02410.05550.00630.01170.0578-0.01070.00220.01250.00250.002721.571414.964810.3707
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A396 - 407
2X-RAY DIFFRACTION1A453 - 476
3X-RAY DIFFRACTION1A418 - 436
4X-RAY DIFFRACTION2A477 - 514
5X-RAY DIFFRACTION2A559 - 658
6X-RAY DIFFRACTION3A437 - 452
7X-RAY DIFFRACTION4A408 - 417
8X-RAY DIFFRACTION5A515 - 558

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