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- PDB-6di1: CRYSTAL STRUCTURE OF BTK IN COMPLEX WITH COVALENT FRAGMENT LIGAND -

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Basic information

Entry
Database: PDB / ID: 6di1
TitleCRYSTAL STRUCTURE OF BTK IN COMPLEX WITH COVALENT FRAGMENT LIGAND
ComponentsTyrosine-protein kinase BTK
KeywordsTRANSFERASE/TRANSFERASE inhibitor / LEAD OPTIMIZATION / FRAGMENT SCREENING BY X-RAY / TRANSFERASE / TRANSFERASE-TRANSFERASE inhibitor complex
Function / homology
Function and homology information


regulation of B cell cytokine production / positive regulation of type III hypersensitivity / histamine secretion by mast cell / B cell affinity maturation / regulation of B cell apoptotic process / cellular response to interleukin-7 / cellular response to molecule of fungal origin / positive regulation of type I hypersensitivity / MyD88 deficiency (TLR2/4) / negative regulation of cytokine production ...regulation of B cell cytokine production / positive regulation of type III hypersensitivity / histamine secretion by mast cell / B cell affinity maturation / regulation of B cell apoptotic process / cellular response to interleukin-7 / cellular response to molecule of fungal origin / positive regulation of type I hypersensitivity / MyD88 deficiency (TLR2/4) / negative regulation of cytokine production / IRAK4 deficiency (TLR2/4) / positive regulation of B cell differentiation / MyD88:MAL(TIRAP) cascade initiated on plasma membrane / MyD88-dependent toll-like receptor signaling pathway / B cell activation / phospholipase activator activity / phosphatidylinositol-3,4,5-trisphosphate binding / mesoderm development / Fc-epsilon receptor signaling pathway / phospholipase binding / negative regulation of B cell proliferation / G beta:gamma signalling through BTK / RHO GTPases Activate WASPs and WAVEs / I-kappaB kinase/NF-kappaB signaling / cell maturation / G alpha (12/13) signalling events / apoptotic signaling pathway / FCERI mediated Ca+2 mobilization / calcium-mediated signaling / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / FCGR3A-mediated phagocytosis / non-specific protein-tyrosine kinase / cellular response to reactive oxygen species / non-membrane spanning protein tyrosine kinase activity / Regulation of actin dynamics for phagocytic cup formation / B cell receptor signaling pathway / G alpha (q) signalling events / peptidyl-tyrosine phosphorylation / DAP12 signaling / ER-Phagosome pathway / cytoplasmic vesicle / adaptive immune response / protein tyrosine kinase activity / positive regulation of NF-kappaB transcription factor activity / intracellular signal transduction / protein autophosphorylation / membrane raft / innate immune response / protein phosphorylation / protein serine/threonine/tyrosine kinase activity / perinuclear region of cytoplasm / ATP binding / metal ion binding / identical protein binding / plasma membrane / nucleus / cytosol / cytoplasm
Similarity search - Function
Tyrosine-protein kinase BTK, SH3 domain / Zinc finger Btk-type profile. / BTK motif / Zinc finger, Btk motif / 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-type profile. / BTK motif / Zinc finger, Btk motif / 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 / SH2 domain superfamily / Src homology 3 domains / SH3-like domain superfamily / Src homology 3 (SH3) domain profile. / SH3 domain / PH-like domain superfamily / Tyrosine kinase, catalytic domain / Tyrosine-protein kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / 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-GJD / Tyrosine-protein kinase BTK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.1 Å
AuthorsJiang, X.
CitationJournal: Bioorg. Med. Chem. Lett. / Year: 2018
Title: Discovery of a novel series of pyridine and pyrimidine carboxamides as potent and selective covalent inhibitors of Btk.
Authors: Caldwell, R. / Liu-Bujalski, L. / Qiu, H. / Mochalkin, I. / Jones, R. / Neagu, C. / Goutopoulos, A. / Grenningloh, R. / Johnson, T. / Sherer, B. / Gardberg, A. / Follis, A.V. / Morandi, F. / Head, J.
History
DepositionMay 22, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 17, 2018Provider: repository / Type: Initial release
Revision 1.1Oct 24, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Tyrosine-protein kinase BTK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,8772
Polymers31,5981
Non-polymers2781
Water7,152397
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)72.250, 104.170, 38.120
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21212

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Components

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


Mass: 31598.287 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens / Gene: BTK, AGMX1, ATK, BPK / Production host: Escherichia coli (E. coli)
References: UniProt: Q06187, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-GJD / 4-amino-2-[(3S)-3-(propanoylamino)pyrrolidin-1-yl]pyrimidine-5-carboxamide


Mass: 278.310 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C12H18N6O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 397 / 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: 2.27 Å3/Da / Density % sol: 45.81 %
Crystal growTemperature: 294 K / Method: vapor diffusion, hanging drop
Details: RESERVOIR SOLUTION : 25% PEG 3350, 0.2M AMMONIUM ACETATE, 0.1M HEPES pH 6.9, 3% GLYCEROL PROTEIN SOLUTION : 10 mg/mL IN 20 mM TRIS, 50 mM NACL, 3 mM DTT, pH 8.0

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Type: OTHER / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 X 1M / Detector: PIXEL / Date: Sep 7, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.1→25 Å / Num. obs: 113484 / % possible obs: 97 % / Redundancy: 5.93 % / Biso Wilson estimate: 13.9 Å2 / CC1/2: 0.999 / Rrim(I) all: 0.045 / Net I/σ(I): 22.36
Reflection shellResolution: 1.102→1.13 Å / Redundancy: 3.34 % / Mean I/σ(I) obs: 5.16 / Num. unique obs: 15536 / CC1/2: 0.963 / Rrim(I) all: 0.216 / % possible all: 83

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Processing

Software
NameVersionClassification
HKL-2000data scaling
REFMAC5.5.0066refinement
PDB_EXTRACT3.24data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.1→25 Å / Cor.coef. Fo:Fc: 0.965 / Cor.coef. Fo:Fc free: 0.961 / SU B: 0.395 / SU ML: 0.02 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.032 / ESU R Free: 0.033
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.1861 5673 5 %RANDOM
Rwork0.1732 ---
obs0.1738 107792 100 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å
Displacement parametersBiso max: 96.56 Å2 / Biso mean: 11.56 Å2 / Biso min: 2.14 Å2
Baniso -1Baniso -2Baniso -3
1-0.57 Å20 Å20 Å2
2---0.26 Å20 Å2
3----0.31 Å2
Refinement stepCycle: final / Resolution: 1.1→25 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2215 0 20 397 2632
Biso mean--15.29 26.67 -
Num. residues----271
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0290.0222321
X-RAY DIFFRACTIONr_bond_other_d00.022062
X-RAY DIFFRACTIONr_angle_refined_deg2.3711.9653135
X-RAY DIFFRACTIONr_angle_other_deg1.6323.0024800
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.0595278
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.62224110
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.66715424
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.2021513
X-RAY DIFFRACTIONr_chiral_restr0.130.2327
X-RAY DIFFRACTIONr_gen_planes_refined0.0140.022573
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02489
LS refinement shellResolution: 1.102→1.13 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.207 314 -
Rwork0.21 5983 -
all-6297 -
obs--100 %

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