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- PDB-4z3v: Fragment-Based Discovery of a Small Molecule Reversible Inhibitor... -

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Basic information

Entry
Database: PDB / ID: 4z3v
TitleFragment-Based Discovery of a Small Molecule Reversible Inhibitor of Bruton's Tyrosine Kinase
ComponentsTyrosine-protein kinase BTK
KeywordsTRANSFERASE / cytoplasmic tyrosine kinase / transcriptional regulation / nuclear factor-kappaB
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 / apoptotic signaling pathway / calcium-mediated signaling / 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 / Src homology 3 domains / SH2 domain / 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-4L6 / IMIDAZOLE / ISOPROPYL ALCOHOL / Tyrosine-protein kinase BTK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.6 Å
AuthorsDougan, D.R.
CitationJournal: J.Med.Chem. / Year: 2015
Title: Fragment-Based Discovery of a Small Molecule Inhibitor of Bruton's Tyrosine Kinase.
Authors: Smith, C.R. / Dougan, D.R. / Komandla, M. / Kanouni, T. / Knight, B. / Lawson, J.D. / Sabat, M. / Taylor, E.R. / Vu, P. / Wyrick, C.
History
DepositionMar 31, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 1, 2015Provider: repository / Type: Initial release
Revision 1.1Aug 5, 2015Group: Database references / Other
Revision 1.2Sep 27, 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 / pdbx_struct_oper_list
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_oper_list.symmetry_operation

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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)33,2696
Polymers32,6911
Non-polymers5795
Water7,314406
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)73.092, 104.100, 38.078
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21212

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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: 32690.506 Da / Num. of mol.: 1 / Fragment: UNP residues 416-693
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BTK, AGMX1, ATK, BPK / Production host: unidentified baculovirus / Strain (production host): sf9
References: UniProt: Q06187, non-specific protein-tyrosine kinase

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Non-polymers , 5 types, 411 molecules

#2: Chemical ChemComp-IMD / IMIDAZOLE / Imidazole


Mass: 69.085 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H5N2
#3: Chemical ChemComp-IPA / ISOPROPYL ALCOHOL / 2-PROPANOL / Isopropyl alcohol


Mass: 60.095 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O / Comment: alkaloid*YM
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical ChemComp-4L6 / 4-amino-8-(5-methyl-1H-indazol-6-yl)cinnoline-3-carboxamide


Mass: 318.333 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H14N6O
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 406 / 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: 2.29 Å3/Da / Density % sol: 46.34 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 10% polyethylene glycol 4000, 20% glycerol, 0.1M imidazole/MES, pH 6.5, 0.12M alcohol mixture

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 23-ID-B / Wavelength: 1.033 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Feb 8, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.033 Å / Relative weight: 1
ReflectionRedundancy: 6.5 % / Number: 267114 / Rmerge(I) obs: 0.097 / Χ2: 1.12 / D res high: 1.55 Å / D res low: 50 Å / Num. obs: 40885 / % possible obs: 95
Diffraction reflection shell
Highest resolution (Å)Lowest resolution (Å)IDRmerge(I) obsChi squaredRedundancy
4.215010.0681.1536.6
3.344.2110.0691.1647
2.923.3410.0851.2347.1
2.652.9210.0851.1667.2
2.462.6510.0911.127.3
2.322.4610.1011.2067.3
2.22.3210.1091.0817.3
2.12.210.1141.0817.3
2.022.110.1221.2167.3
1.952.0210.1351.1087.3
1.891.9510.1651.1977.3
1.841.8910.1991.0967.3
1.791.8410.2211.0497.3
1.751.7910.2491.0677.1
1.711.7510.2941.0326.6
1.671.7110.3151.0055.2
1.641.6710.3471.0124.4
1.611.6410.3711.0513.9
1.581.6110.3521.0433.6
1.551.5810.4021.0933.2
ReflectionResolution: 1.55→50 Å / Num. obs: 40885 / % possible obs: 95 % / Redundancy: 6.5 % / Rmerge(I) obs: 0.097 / Χ2: 1.12 / Net I/av σ(I): 19.467 / Net I/σ(I): 9.5 / Num. measured all: 267114

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation2.5 Å32.12 Å
Translation2.5 Å32.12 Å

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Processing

Software
NameVersionClassification
HKL-2000data reduction
HKL-2000data scaling
SCALEPACKdata scaling
PHASER2.3.0phasing
REFMAC5.7.0025refinement
PDB_EXTRACT3.15data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 3GEN

3gen


Resolution: 1.6→30 Å / Cor.coef. Fo:Fc: 0.963 / Cor.coef. Fo:Fc free: 0.951 / SU B: 2.881 / SU ML: 0.052 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.089 / ESU R Free: 0.089 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT
RfactorNum. reflection% reflectionSelection details
Rfree0.1975 1914 5 %RANDOM
Rwork0.1646 ---
obs0.1663 36431 97.76 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 63.39 Å2 / Biso mean: 17.847 Å2 / Biso min: 5.25 Å2
Baniso -1Baniso -2Baniso -3
1-1.05 Å20 Å20 Å2
2---0.47 Å20 Å2
3----0.58 Å2
Refinement stepCycle: final / Resolution: 1.6→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2214 0 42 406 2662
Biso mean--20.02 31.65 -
Num. residues----271
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0192389
X-RAY DIFFRACTIONr_angle_refined_deg1.2861.9763218
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.4625270
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.86624.103117
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.77815454
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.5971514
X-RAY DIFFRACTIONr_chiral_restr0.1070.2341
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0211794
LS refinement shellResolution: 1.6→1.642 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.242 122 -
Rwork0.226 2153 -
all-2275 -
obs--80.76 %
Refinement TLS params.Method: refined / Origin x: -16.3156 Å / Origin y: -15.7788 Å / Origin z: 5.9054 Å
111213212223313233
T0.0046 Å20.0013 Å20.0022 Å2-0.0105 Å20.0007 Å2--0.0027 Å2
L0.2054 °2-0.0009 °20.0408 °2-0.394 °2-0.0145 °2--0.2826 °2
S-0.0005 Å °-0.0253 Å °0.0115 Å °0.0078 Å °0.0174 Å °-0.008 Å °-0.0352 Å °-0.0145 Å °-0.0169 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A389 - 492
2X-RAY DIFFRACTION1A493 - 552
3X-RAY DIFFRACTION1A556 - 658
4X-RAY DIFFRACTION1A701
5X-RAY DIFFRACTION1A703
6X-RAY DIFFRACTION1A705

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