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- PDB-6yyk: Crystal Structure of 1,5-dimethylindoline-2,3-dione covalently bo... -

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Basic information

Entry
Database: PDB / ID: 6yyk
TitleCrystal Structure of 1,5-dimethylindoline-2,3-dione covalently bound to the PH domain of Bruton's tyrosine kinase mutant R28C
ComponentsTyrosine-protein kinase BTK
KeywordsTRANSFERASE / BTK / Covalent fragments / surface entrophy reduction / crystal engineering
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 / calcium-mediated signaling / apoptotic signaling pathway / 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 / 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 / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
1,5-dimethyl-3~{H}-indol-2-one / Tyrosine-protein kinase BTK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.04 Å
AuthorsBrear, P. / Wagstaff, J. / Hyvonen, M.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Medical Research Council (MRC, United Kingdom) United Kingdom
CitationJournal: To Be Published
Title: Optimising crystallographic systems for structure-guided drug discovery
Authors: Brear, P. / Fischer, G. / May, M. / Pantelejevs, T. / Mathieu, R. / Rossmann, M. / Wagstaff, J. / Blaszczyk, B. / Hyvonen, M.
History
DepositionMay 5, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 12, 2021Provider: repository / Type: Initial release
Revision 1.1Jan 24, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Tyrosine-protein kinase BTK
B: Tyrosine-protein kinase BTK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)40,1997
Polymers39,8582
Non-polymers3415
Water54030
1
A: Tyrosine-protein kinase BTK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,0193
Polymers19,9291
Non-polymers902
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Tyrosine-protein kinase BTK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,1804
Polymers19,9291
Non-polymers2513
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)48.199, 60.344, 58.058
Angle α, β, γ (deg.)90.000, 96.570, 90.000
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 19928.963 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BTK, AGMX1, ATK, BPK / Plasmid: pBAT4 / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: Q06187, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-IS7 / 1,5-dimethyl-3~{H}-indol-2-one


Mass: 161.200 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H11NO / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 30 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.1 Å3/Da / Density % sol: 41.55 % / Mosaicity: 0 °
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: 0.1 M TRIS 8.5 pH, 32.5% w/v PEG 3350, 200mM MgCl2 500 mM NaCl

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.9795 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Apr 3, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.04→60.41 Å / Num. obs: 21231 / % possible obs: 99.8 % / Redundancy: 3.2 % / CC1/2: 0.996 / Rmerge(I) obs: 0.074 / Rpim(I) all: 0.049 / Rrim(I) all: 0.09 / Net I/σ(I): 5.3 / Num. measured all: 67401 / Scaling rejects: 11
Reflection shell

Diffraction-ID: 1 / Redundancy: 3 %

Resolution (Å)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.04-2.091.346469215630.6610.9211.6370.799.6
9.12-60.410.0527902670.9940.0350.06318.999.8

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
REFMAC5.8.0238refinement
XDSdata reduction
Aimless0.5.31data scaling
PHASERphasing
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1BTK

1btk


Resolution: 2.04→57.74 Å / Cor.coef. Fo:Fc: 0.961 / Cor.coef. Fo:Fc free: 0.931 / SU B: 15.021 / SU ML: 0.333 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.259 / ESU R Free: 0.228 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2964 1021 4.9 %RANDOM
Rwork0.2275 ---
obs0.2307 19781 97.49 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 203.38 Å2 / Biso mean: 67.47 Å2 / Biso min: 36.46 Å2
Baniso -1Baniso -2Baniso -3
1-3.05 Å20 Å28.03 Å2
2---4.47 Å20 Å2
3----0.42 Å2
Refinement stepCycle: final / Resolution: 2.04→57.74 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2631 0 16 30 2677
Biso mean--84.57 59.38 -
Num. residues----317
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0132716
X-RAY DIFFRACTIONr_bond_other_d0.0010.0172538
X-RAY DIFFRACTIONr_angle_refined_deg1.5631.6523666
X-RAY DIFFRACTIONr_angle_other_deg1.2071.585911
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.7245314
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.96121.788151
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.1415497
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.731520
X-RAY DIFFRACTIONr_chiral_restr0.0710.2340
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.023020
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02584
LS refinement shellResolution: 2.04→2.089 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.515 69 -
Rwork0.444 1298 -
obs--87.29 %

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