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- PDB-6di5: CRYSTAL STRUCTURE OF BTK IN COMPLEX WITH COVALENT INHIBITOR -

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Basic information

Entry
Database: PDB / ID: 6di5
TitleCRYSTAL STRUCTURE OF BTK IN COMPLEX WITH COVALENT INHIBITOR
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 / 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 / negative regulation of B cell proliferation / Fc-epsilon receptor signaling pathway / B cell activation / mesoderm development / phosphatidylinositol-3,4,5-trisphosphate binding / phospholipase binding / 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 / apoptotic signaling pathway / FCGR3A-mediated phagocytosis / B cell receptor signaling pathway / non-specific protein-tyrosine kinase / calcium-mediated signaling / non-membrane spanning protein tyrosine kinase activity / Regulation of actin dynamics for phagocytic cup formation / G beta:gamma signalling through BTK / peptidyl-tyrosine phosphorylation / positive regulation of interleukin-6 production / cellular response to reactive oxygen species / 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 / protein tyrosine kinase activity / G alpha (q) signalling events / 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 / 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 / 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-GJ7 / Tyrosine-protein kinase BTK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.42 Å
AuthorsGardberg, A.
CitationJournal: Bioorg. Med. Chem. Lett. / Year: 2018
Title: Discovery of potent, highly selective covalent irreversible BTK inhibitors from a fragment hit.
Authors: Qiu, H. / Liu-Bujalski, L. / Caldwell, R.D. / Follis, A.V. / Gardberg, A. / Goutopoulos, A. / Grenningloh, R. / Head, J. / Johnson, T. / Jones, R. / Mochalkin, I. / Morandi, F. / Neagu, C. / Sherer, B.
History
DepositionMay 22, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 5, 2018Provider: repository / Type: Initial release
Revision 1.1Nov 20, 2024Group: Data collection / Database references / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature
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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,1353
Polymers31,5981
Non-polymers5372
Water5,531307
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)74.033, 107.696, 39.320
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 (human) / Gene: BTK, AGMX1, ATK, BPK / Production host: Escherichia coli (E. coli)
References: UniProt: Q06187, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-GJ7 / 2-(4-phenoxyphenoxy)-6-[(1S,4S)-5-propanoyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]pyridine-3-carboxamide


Mass: 458.509 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H26N4O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 307 / Source method: isolated from a natural source / Formula: H2O
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: 2.48 Å3/Da / Density % sol: 50.41 %
Crystal growTemperature: 294 K / Method: vapor diffusion, hanging drop
Details: 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: X10SA / Wavelength: 1.033 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 30, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.033 Å / Relative weight: 1
ReflectionResolution: 1.42→50 Å / Num. obs: 59227 / % possible obs: 98.4 % / Redundancy: 6.5 % / Rmerge(I) obs: 0.044 / Net I/σ(I): 23.9
Reflection shellResolution: 1.42→1.51 Å / Redundancy: 6.48 % / Rmerge(I) obs: 0.57 / Mean I/σ(I) obs: 3.21 / % possible all: 95.9

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Processing

Software
NameVersionClassification
HKL-2000data scaling
REFMAC5.5.0066refinement
PDB_EXTRACT3.24data extraction
RefinementResolution: 1.42→43.55 Å / Cor.coef. Fo:Fc: 0.959 / Cor.coef. Fo:Fc free: 0.953 / SU B: 1.871 / SU ML: 0.034 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.06 / ESU R Free: 0.06 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.1947 2962 5 %RANDOM
Rwork0.1778 ---
obs0.1786 56265 100 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å
Displacement parametersBiso max: 58.45 Å2 / Biso mean: 12.364 Å2 / Biso min: 4.99 Å2
Baniso -1Baniso -2Baniso -3
1-0.82 Å20 Å20 Å2
2---0.4 Å20 Å2
3----0.41 Å2
Refinement stepCycle: final / Resolution: 1.42→43.55 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2160 0 38 307 2505
Biso mean--17.24 25.59 -
Num. residues----271
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0270.0222289
X-RAY DIFFRACTIONr_bond_other_d0.0010.022015
X-RAY DIFFRACTIONr_angle_refined_deg1.7811.9843103
X-RAY DIFFRACTIONr_angle_other_deg2.08334689
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.1685282
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.35123.96101
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.96115404
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.291512
X-RAY DIFFRACTIONr_chiral_restr0.120.2329
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.022537
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02469
LS refinement shellResolution: 1.42→1.457 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.297 207 -
Rwork0.272 3930 -
all-4137 -
obs--100 %

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