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- PDB-5t18: Crystal structure of Bruton agammabulinemia tyrosine kinase compl... -

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Basic information

Entry
Database: PDB / ID: 5t18
TitleCrystal structure of Bruton agammabulinemia tyrosine kinase complexed with BMS-986142 aka (2s)-6-fluoro-5-[3-(8-fluoro-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl)-2-methylphenyl]-2-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1h-carbazole-8-carboxamide
ComponentsTyrosine-protein kinase BTK
KeywordsTRANSFERASE / KINASE / BTK / ATK / XLA / PSCTK1 / AGMX1 / AT / IMD1 / MGC126261 / MGC126262 BPK / ----
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 / positive regulation of synoviocyte proliferation / histamine secretion by mast cell ...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 / positive regulation of synoviocyte proliferation / histamine secretion by mast cell / neutrophil homeostasis / cellular response to molecule of fungal origin / positive regulation of type I hypersensitivity / MyD88 deficiency (TLR2/4) / cellular response to interleukin-7 / MyD88-dependent toll-like receptor signaling pathway / IRAK4 deficiency (TLR2/4) / MyD88:MAL(TIRAP) cascade initiated on plasma membrane / positive regulation of immunoglobulin production / positive regulation of B cell differentiation / positive regulation of NLRP3 inflammasome complex assembly / phospholipase activator activity / negative regulation of interleukin-10 production / negative regulation of B cell proliferation / mesoderm development / Fc-epsilon receptor signaling pathway / B cell activation / phosphatidylinositol-3,4,5-trisphosphate binding / phospholipase binding / 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 / apoptotic signaling pathway / non-specific protein-tyrosine kinase / FCGR3A-mediated phagocytosis / B cell receptor signaling pathway / non-membrane spanning protein tyrosine kinase activity / calcium-mediated signaling / Regulation of actin dynamics for phagocytic cup formation / peptidyl-tyrosine phosphorylation / G beta:gamma signalling through BTK / positive regulation of interleukin-6 production / cellular response to reactive oxygen species / positive regulation of tumor necrosis factor production / G alpha (12/13) signalling events / DAP12 signaling / positive regulation of NF-kappaB transcription factor activity / T cell receptor signaling pathway / ER-Phagosome pathway / cytoplasmic vesicle / protein tyrosine kinase activity / G alpha (q) signalling events / adaptive immune response / response to lipopolysaccharide / Potential therapeutics for SARS / intracellular signal transduction / protein phosphorylation / membrane raft / innate immune response / perinuclear region of cytoplasm / ATP binding / identical protein binding / nucleus / metal ion binding / 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. / Tyrosine-protein kinase, active site / PH-like domain superfamily / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / 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-73T / Tyrosine-protein kinase BTK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.5 Å
AuthorsMuckelbauer, J.K.
CitationJournal: J. Med. Chem. / Year: 2016
Title: Discovery of 6-Fluoro-5-(R)-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-2-(S)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide (BMS- ...Title: Discovery of 6-Fluoro-5-(R)-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-2-(S)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide (BMS-986142): A Reversible Inhibitor of Bruton's Tyrosine Kinase (BTK) Conformationally Constrained by Two Locked Atropisomers.
Authors: Watterson, S.H. / De Lucca, G.V. / Shi, Q. / Langevine, C.M. / Liu, Q. / Batt, D.G. / Beaudoin Bertrand, M. / Gong, H. / Dai, J. / Yip, S. / Li, P. / Sun, D. / Wu, D.R. / Wang, C. / Zhang, Y. ...Authors: Watterson, S.H. / De Lucca, G.V. / Shi, Q. / Langevine, C.M. / Liu, Q. / Batt, D.G. / Beaudoin Bertrand, M. / Gong, H. / Dai, J. / Yip, S. / Li, P. / Sun, D. / Wu, D.R. / Wang, C. / Zhang, Y. / Traeger, S.C. / Pattoli, M.A. / Skala, S. / Cheng, L. / Obermeier, M.T. / Vickery, R. / Discenza, L.N. / D'Arienzo, C.J. / Zhang, Y. / Heimrich, E. / Gillooly, K.M. / Taylor, T.L. / Pulicicchio, C. / McIntyre, K.W. / Galella, M.A. / Tebben, A.J. / Muckelbauer, J.K. / Chang, C. / Rampulla, R. / Mathur, A. / Salter-Cid, L. / Barrish, J.C. / Carter, P.H. / Fura, A. / Burke, J.R. / Tino, J.A.
History
DepositionAug 18, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 8, 2017Provider: repository / Type: Initial release
Revision 1.1Mar 6, 2024Group: Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / diffrn_radiation_wavelength
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)31,7772
Polymers31,2041
Non-polymers5731
Water2,648147
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area11780 Å2
MethodPISA
Unit cell
Length a, b, c (Å)46.604, 69.759, 88.955
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 31203.910 Da / Num. of mol.: 1 / Fragment: kinase domain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BTK, AGMX1, ATK, BPK / Production host: baculovirus / Strain (production host): sf9
References: UniProt: Q06187, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-73T / 6-Fluoro-5-(R)-(3-(S)-(8-fluoro-1-methyl-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)-2-methylphenyl)-2-(S)-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide / (2S)-6-fluoro-5-[3-(8-fluoro-1-methyl-2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl)-2-methylphenyl]-2-(2-hydroxypropan-2-yl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide


Mass: 572.602 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C32H30F2N4O4
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 147 / 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: 2.32 Å3/Da / Density % sol: 46.91 % / Mosaicity: 0.461 °
Crystal growTemperature: 298 K / Method: vapor diffusion / pH: 7 / Details: 25% PEG8K + 3% MEPEG5K + 0.2M TRIS-HCL, PH 7.0

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: CLSI / Beamline: 08ID-1 / Wavelength: 0.98 Å
DetectorType: RAYONIX MX-300 / Detector: CCD / Date: May 24, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 1.5→50 Å / Num. obs: 46852 / % possible obs: 99.6 % / Observed criterion σ(I): 0 / Redundancy: 5.9 % / Biso Wilson estimate: 23.37 Å2 / Rmerge(I) obs: 0.071 / Χ2: 1.047 / Net I/av σ(I): 21.334 / Net I/σ(I): 21.3 / Num. measured all: 276987
Reflection shellResolution: 1.5→1.55 Å / Redundancy: 6 % / Rmerge(I) obs: 0.627 / Mean I/σ(I) obs: 3.7 / % possible all: 100

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Processing

Software
NameVersionClassification
BUSTER-TNT2.11.7refinement
SCALEPACKdata scaling
PDB_EXTRACT3.2data extraction
RefinementResolution: 1.5→30 Å / Cor.coef. Fo:Fc: 0.952 / Cor.coef. Fo:Fc free: 0.949 / Rfactor Rfree error: 0 / SU R Cruickshank DPI: 0.081 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.074 / SU Rfree Blow DPI: 0.073 / SU Rfree Cruickshank DPI: 0.072
RfactorNum. reflection% reflectionSelection details
Rfree0.223 2364 5.05 %RANDOM
Rwork0.203 ---
obs0.204 46785 99.1 %-
Displacement parametersBiso max: 75.89 Å2 / Biso mean: 24.9 Å2 / Biso min: 11.61 Å2
Baniso -1Baniso -2Baniso -3
1--1.4472 Å20 Å20 Å2
2--0.8509 Å20 Å2
3---0.5963 Å2
Refine analyzeLuzzati coordinate error obs: 0.2 Å
Refinement stepCycle: final / Resolution: 1.5→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1974 0 72 147 2193
Biso mean--18.21 33.7 -
Num. residues----261
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d832SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes34HARMONIC2
X-RAY DIFFRACTIONt_gen_planes644HARMONIC5
X-RAY DIFFRACTIONt_it3932HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion269SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact4375SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d3932HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg7064HARMONIC21.06
X-RAY DIFFRACTIONt_omega_torsion4.07
X-RAY DIFFRACTIONt_other_torsion13.45
LS refinement shellResolution: 1.5→1.54 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.262 176 5.52 %
Rwork0.211 3013 -
all-3189 -
obs--93.37 %

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