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- PDB-6tse: Crystal Structure of 1-methylindoline-2,3-dione covalently bound ... -

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Basic information

Entry
Database: PDB / ID: 6tse
TitleCrystal Structure of 1-methylindoline-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 / 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 / cellular response to interleukin-7 / MyD88 deficiency (TLR2/4) / MyD88-dependent toll-like receptor signaling pathway / IRAK4 deficiency (TLR2/4) / positive regulation of immunoglobulin production / 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 / mesoderm development / phosphatidylinositol-3,4,5-trisphosphate binding / phospholipase binding / RHO GTPases Activate WASPs and WAVEs / positive regulation of B cell proliferation / positive regulation of phagocytosis / 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 / Regulation of actin dynamics for phagocytic cup formation / G beta:gamma signalling through BTK / cellular response to reactive oxygen species / peptidyl-tyrosine phosphorylation / positive regulation of interleukin-6 production / 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 / G alpha (q) signalling events / protein tyrosine kinase activity / adaptive immune response / Potential therapeutics for SARS / response to lipopolysaccharide / intracellular signal transduction / membrane raft / protein phosphorylation / innate immune response / perinuclear region of cytoplasm / ATP binding / identical protein binding / nucleus / metal ion binding / plasma membrane / cytoplasm / cytosol
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-methylindole-2,3-dione / Tyrosine-protein kinase BTK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.41 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
DepositionDec 20, 2019Deposition 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

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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)40,68210
Polymers39,8582
Non-polymers8248
Water4,035224
1
A: Tyrosine-protein kinase BTK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)20,5026
Polymers19,9291
Non-polymers5735
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)47.070, 60.594, 57.846
Angle α, β, γ (deg.)90.000, 98.650, 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 / Fragment: PH DOMAIN AND BTK MOTIF / Mutation: R28C
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-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#3: Chemical
ChemComp-72V / 1-methylindole-2,3-dione


Mass: 161.157 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C9H7NO2 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: Zn
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 224 / 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: 2.05 Å3/Da / Density % sol: 39.89 % / 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, 500mM NaCl

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.9763 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 2, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9763 Å / Relative weight: 1
ReflectionResolution: 1.41→60.59 Å / Num. obs: 61717 / % possible obs: 99.6 % / Redundancy: 3.2 % / Biso Wilson estimate: 19 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.048 / Rpim(I) all: 0.031 / Rrim(I) all: 0.057 / Net I/σ(I): 10.2 / Num. measured all: 195102 / Scaling rejects: 62
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
1.41-1.452.50.8031112044230.5980.5760.9921.197
6.31-60.593.30.04124277410.9960.0270.0528.299.9

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Processing

Software
NameVersionClassification
BUSTER2.10.3refinement
Aimless0.5.31data scaling
PDB_EXTRACT3.25data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1BTK

1btk


Resolution: 1.41→57.19 Å / Cor.coef. Fo:Fc: 0.954 / Cor.coef. Fo:Fc free: 0.942 / SU R Cruickshank DPI: 0.07 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.07 / SU Rfree Blow DPI: 0.07 / SU Rfree Cruickshank DPI: 0.07
RfactorNum. reflection% reflectionSelection details
Rfree0.224 2950 4.86 %RANDOM
Rwork0.201 ---
obs0.202 60643 97.8 %-
Displacement parametersBiso max: 139.25 Å2 / Biso mean: 28.53 Å2 / Biso min: 9.75 Å2
Baniso -1Baniso -2Baniso -3
1-2.3098 Å20 Å2-3.5373 Å2
2---0.2738 Å20 Å2
3----2.036 Å2
Refinement stepCycle: final / Resolution: 1.41→57.19 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2643 0 49 224 2916
Biso mean--33.32 33.82 -
Num. residues----318
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d974SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes69HARMONIC2
X-RAY DIFFRACTIONt_gen_planes444HARMONIC5
X-RAY DIFFRACTIONt_it2780HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion343SEMIHARMONIC5
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_contact3245SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2780HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg3755HARMONIC21.07
X-RAY DIFFRACTIONt_omega_torsion4.36
X-RAY DIFFRACTIONt_other_torsion16.5
LS refinement shellResolution: 1.41→1.45 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.3022 195 4.86 %
Rwork0.2657 3821 -
all0.2675 4016 -
obs--88.27 %

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