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- PDB-6yyg: Crystal Structure of 5-(trifluoromethoxy)indoline-2,3-dione coval... -

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Basic information

Entry
Database: PDB / ID: 6yyg
TitleCrystal Structure of 5-(trifluoromethoxy)indoline-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 / 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 / adaptive immune response / Potential therapeutics for SARS / 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 / 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. / PH-like domain superfamily / Tyrosine-protein kinase, active site / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / 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
5-(trifluoromethyloxy)-1,3-dihydroindol-2-one / Tyrosine-protein kinase BTK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.95 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
Revision 1.2Nov 6, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)80,89413
Polymers79,9324
Non-polymers9629
Water3,639202
1
A: Tyrosine-protein kinase BTK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,2904
Polymers19,9831
Non-polymers3073
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Tyrosine-protein kinase BTK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,2663
Polymers19,9831
Non-polymers2832
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Tyrosine-protein kinase BTK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,0482
Polymers19,9831
Non-polymers651
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Tyrosine-protein kinase BTK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,2904
Polymers19,9831
Non-polymers3073
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)68.649, 67.195, 79.641
Angle α, β, γ (deg.)90.000, 99.660, 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: 19983.014 Da / Num. of mol.: 4
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-Q1B / 5-(trifluoromethyloxy)-1,3-dihydroindol-2-one


Mass: 217.145 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C9H6F3NO2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#4: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Zn
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 202 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 2.27 Å3/Da / Density % sol: 45.71 % / 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: I24 / Wavelength: 0.9797 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: May 23, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9797 Å / Relative weight: 1
ReflectionResolution: 1.95→51.06 Å / Num. obs: 52358 / % possible obs: 100 % / Redundancy: 10.8 % / CC1/2: 0.997 / Rmerge(I) obs: 0.145 / Rpim(I) all: 0.046 / Rrim(I) all: 0.152 / Net I/σ(I): 8.6 / Num. measured all: 563050 / Scaling rejects: 94
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
1.95-29.42.3363653738710.6480.8032.4741.1100
8.72-51.0610.20.1163516200.9940.0360.11524.899.6

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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: 1.95→51.05 Å / Cor.coef. Fo:Fc: 0.953 / Cor.coef. Fo:Fc free: 0.916 / SU B: 8.414 / SU ML: 0.214 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.206 / ESU R Free: 0.199
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2988 2575 5 %RANDOM
Rwork0.2304 ---
obs0.2338 49164 98.78 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 127.74 Å2 / Biso mean: 41.561 Å2 / Biso min: 15.68 Å2
Baniso -1Baniso -2Baniso -3
1-1.69 Å20 Å2-0.35 Å2
2--1.88 Å20 Å2
3----3.26 Å2
Refinement stepCycle: final / Resolution: 1.95→51.05 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5206 0 51 202 5459
Biso mean--59.26 41.29 -
Num. residues----624
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0135412
X-RAY DIFFRACTIONr_bond_other_d0.0010.0175048
X-RAY DIFFRACTIONr_angle_refined_deg1.5881.6537302
X-RAY DIFFRACTIONr_angle_other_deg1.221.58111747
X-RAY DIFFRACTIONr_dihedral_angle_1_deg8.2635619
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.52721.613310
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.17815993
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.8071543
X-RAY DIFFRACTIONr_chiral_restr0.0760.2673
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.026005
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021184
LS refinement shellResolution: 1.95→1.999 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.438 173 -
Rwork0.422 3518 -
obs--95.33 %

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