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- PDB-6tvn: Crystal Structure of 5-bromoindoline-2,3-dione covalently bound t... -

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Basic information

Entry
Database: PDB / ID: 6tvn
TitleCrystal Structure of 5-bromoindoline-2,3-dione covalently bound to the PH domain of Bruton's tyrosine kinase
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
5-bromanyl-1,3-dihydroindol-2-one / Tyrosine-protein kinase BTK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.31 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: Crystal Structure of 1-methylindoline-2,3-dione covalently bound to the PH domain of Bruton's tyrosine kinase mutant R28C
Authors: Brear, P. / Fischer, G. / May, M. / Pantelejevs, T. / Mathieu, R. / Rossmann, M. / Wagstaff, J. / Blaszczyk, B. / Hyvonen, M.
History
DepositionJan 10, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 25, 2020Provider: 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
C: Tyrosine-protein kinase BTK
D: Tyrosine-protein kinase BTK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)80,96214
Polymers79,8044
Non-polymers1,15810
Water61334
1
A: Tyrosine-protein kinase BTK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,2534
Polymers19,9511
Non-polymers3023
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Tyrosine-protein kinase BTK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,2283
Polymers19,9511
Non-polymers2772
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Tyrosine-protein kinase BTK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,2283
Polymers19,9511
Non-polymers2772
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Tyrosine-protein kinase BTK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,2534
Polymers19,9511
Non-polymers3023
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)67.775, 65.400, 79.752
Angle α, β, γ (deg.)90.000, 101.340, 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: 19950.949 Da / Num. of mol.: 4 / Fragment: PH DOMAIN AND BTK MOTIF / Mutation: C145A
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-NYQ / 5-bromanyl-1,3-dihydroindol-2-one


Mass: 212.043 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C8H6BrNO / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Zn
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 34 / 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: 2.17 Å3/Da / Density % sol: 43.36 % / 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

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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: Sep 13, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.31→66.45 Å / Num. obs: 30254 / % possible obs: 100 % / Redundancy: 6.7 % / Biso Wilson estimate: 50.62 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.096 / Rpim(I) all: 0.04 / Rrim(I) all: 0.104 / Net I/σ(I): 11.7 / Num. measured all: 201455 / Scaling rejects: 301
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
2.31-2.376.61.6591457222240.5350.7011.8041.5100
10.33-66.456.10.03622403690.9990.0160.0435.399.7

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Processing

Software
NameVersionClassification
BUSTER2.10.3refinement
Aimless0.5.32data scaling
PDB_EXTRACT3.25data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1BTK

1btk


Resolution: 2.31→66.45 Å / Cor.coef. Fo:Fc: 0.933 / Cor.coef. Fo:Fc free: 0.911 / SU R Cruickshank DPI: 0.393 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.362 / SU Rfree Blow DPI: 0.238 / SU Rfree Cruickshank DPI: 0.247
RfactorNum. reflection% reflectionSelection details
Rfree0.257 1494 4.96 %RANDOM
Rwork0.225 ---
obs0.227 30112 99.5 %-
Displacement parametersBiso max: 136.23 Å2 / Biso mean: 53.75 Å2 / Biso min: 12.75 Å2
Baniso -1Baniso -2Baniso -3
1--3.4849 Å20 Å2-3.1081 Å2
2---3.4123 Å20 Å2
3---6.8972 Å2
Refinement stepCycle: final / Resolution: 2.31→66.45 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5124 0 50 36 5210
Biso mean--68.59 34.63 -
Num. residues----615
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1897SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes127HARMONIC2
X-RAY DIFFRACTIONt_gen_planes790HARMONIC5
X-RAY DIFFRACTIONt_it5341HARMONIC20
X-RAY DIFFRACTIONt_nbd5SEMIHARMONIC5
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion664SEMIHARMONIC5
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_contact5848SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d5341HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg7210HARMONIC21.11
X-RAY DIFFRACTIONt_omega_torsion3.62
X-RAY DIFFRACTIONt_other_torsion18.69
LS refinement shellResolution: 2.31→2.39 Å / Rfactor Rfree error: 0 / Total num. of bins used: 15
RfactorNum. reflection% reflection
Rfree0.3657 149 5.09 %
Rwork0.3122 2781 -
all0.3149 2930 -
obs--98.62 %

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