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- PDB-4rfz: Crystal structure of BTK kinase domain complexed with 6-(dimethyl... -

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Basic information

Entry
Database: PDB / ID: 4rfz
TitleCrystal structure of BTK kinase domain complexed with 6-(dimethylamino)-8-fluoro-2-[2-(hydroxymethyl)-3-[1-methyl-5-[[5-(morpholine-4-carbonyl)-2-pyridyl]amino]-6-oxo-3-pyridyl]phenyl]isoquinolin-1-one
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 / cell maturation / phospholipase binding / 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-3OV / Tyrosine-protein kinase BTK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.17 Å
AuthorsKuglstatter, A. / Wong, A.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2015
Title: Finding the perfect spot for fluorine: Improving potency up to 40-fold during a rational fluorine scan of a Bruton's Tyrosine Kinase (BTK) inhibitor scaffold.
Authors: Lou, Y. / Sweeney, Z.K. / Kuglstatter, A. / Davis, D. / Goldstein, D.M. / Han, X. / Hong, J. / Kocer, B. / Kondru, R.K. / Litman, R. / McIntosh, J. / Sarma, K. / Suh, J. / Taygerly, J. / Owens, T.D.
History
DepositionSep 29, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 24, 2014Provider: repository / Type: Initial release
Revision 1.1Jan 14, 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)33,3024
Polymers32,5211
Non-polymers7813
Water5,296294
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)71.936, 106.197, 38.220
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212
Components on special symmetry positions
IDModelComponents
11A-842-

HOH

21A-904-

HOH

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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: protein kinase domain (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-3OV / 6-(dimethylamino)-8-fluoro-2-[2-(hydroxymethyl)-3-(1-methyl-5-{[5-(morpholin-4-ylcarbonyl)pyridin-2-yl]amino}-6-oxo-1,6-dihydropyridin-3-yl)phenyl]isoquinolin-1(2H)-one


Mass: 624.661 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C34H33FN6O5
#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.: 294 / 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: 2.24 Å3/Da / Density % sol: 45.2 %
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: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD
RadiationMonochromator: liquid nitrogen cooled dual crystal Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.17→50 Å / Num. obs: 86470 / % possible obs: 87.5 % / Redundancy: 4.8 % / Biso Wilson estimate: 10.6 Å2 / Rsym value: 0.046 / Net I/σ(I): 21.8
Reflection shellResolution: 1.17→1.21 Å / Redundancy: 2.8 % / Mean I/σ(I) obs: 1.8 / Rsym value: 0.432 / % possible all: 38.1

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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 4OTR

4otr


Resolution: 1.17→42.72 Å / Cor.coef. Fo:Fc: 0.972 / Cor.coef. Fo:Fc free: 0.967 / SU B: 1.379 / SU ML: 0.027 / Cross valid method: THROUGHOUT / ESU R: 0.04 / ESU R Free: 0.04 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.18357 4344 5 %RANDOM
Rwork0.15659 ---
obs0.15791 82059 87.11 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 18.282 Å2
Baniso -1Baniso -2Baniso -3
1-0.82 Å20 Å2-0 Å2
2---0.31 Å2-0 Å2
3----0.51 Å2
Refinement stepCycle: LAST / Resolution: 1.17→42.72 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2139 0 54 294 2487
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0210.0192245
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.9831.9863031
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.9725262
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.93524.135104
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.5215401
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.6871512
X-RAY DIFFRACTIONr_chiral_restr0.1370.2318
X-RAY DIFFRACTIONr_gen_planes_refined0.0140.0211716
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_it1.7741.0881051
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it2.1051.6421312
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it3.2871.4221194
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined3.55211.3533802
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr8.57232245
X-RAY DIFFRACTIONr_sphericity_free24.834585
X-RAY DIFFRACTIONr_sphericity_bonded9.46352402
LS refinement shellResolution: 1.17→1.202 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.35 118 -
Rwork0.345 2189 -
obs--31.7 %
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)
10.1607-0.00360.1392.34380.04660.21230.02860.0029-0.0792-0.01660.04810.04810.07350.005-0.07680.0733-0.00150.00040.0012-0.00180.050119.3138-2.17097.8385
20.29120.0032-0.11310.2796-0.08090.67010.0063-0.00590.0299-0.00050.01310.0156-0.0461-0.0117-0.01940.02490.00050.00090.01340.00060.0119.472927.04162.7142
38.1392-2.06481.49961.778-1.31042.22680.0640.1109-0.56390.07260.02280.09940.0765-0.2106-0.08680.0534-0.01950.00260.0337-0.00850.044916.82024.975219.6017
41.64840.55261.37262.18742.14655.4762-0.05230.0262-0.07710.02260.058-0.1614-0.01670.136-0.00570.0241-0.00110.00920.0035-0.00060.028629.12243.81117.2227
50.4302-0.07150.25590.3623-0.31381.3642-0.021-0.0186-0.01330.0284-0.0109-0.01440.02580.01810.03190.0378-0.0002-0.00120.00730.00470.00822.081714.704410.318
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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