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- PDB-7kxo: BTK1 SOAKED WITH COMPOUND 24 -

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Basic information

Entry
Database: PDB / ID: 7kxo
TitleBTK1 SOAKED WITH COMPOUND 24
ComponentsIsoform BTK-C of Tyrosine-protein kinase BTK
KeywordsTRANSFERASE
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 / cell maturation / phospholipase binding / 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 / Potential therapeutics for SARS / adaptive immune response / 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 / 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 ...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 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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-X9S / Tyrosine-protein kinase BTK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.94 Å
AuthorsViacava Follis, A.
CitationJournal: Bioorg.Med.Chem. / Year: 2021
Title: Discovery of potent and selective reversible Bruton's tyrosine kinase inhibitors.
Authors: Qiu, H. / Ali, Z. / Bender, A. / Caldwell, R. / Chen, Y.Y. / Fang, Z. / Gardberg, A. / Glaser, N. / Goettsche, A. / Goutopoulos, A. / Grenningloh, R. / Hanschke, B. / Head, J. / Johnson, T. ...Authors: Qiu, H. / Ali, Z. / Bender, A. / Caldwell, R. / Chen, Y.Y. / Fang, Z. / Gardberg, A. / Glaser, N. / Goettsche, A. / Goutopoulos, A. / Grenningloh, R. / Hanschke, B. / Head, J. / Johnson, T. / Jones, C. / Jones, R. / Kulkarni, S. / Maurer, C. / Morandi, F. / Neagu, C. / Poetzsch, S. / Potnick, J. / Schmidt, R. / Roe, K. / Viacava Follis, A. / Wing, C. / Zhu, X. / Sherer, B.
History
DepositionDec 4, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 19, 2021Provider: repository / Type: Initial release
Revision 1.1Oct 18, 2023Group: 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: Isoform BTK-C of Tyrosine-protein kinase BTK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,1797
Polymers31,2081
Non-polymers9716
Water2,342130
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)72.760, 103.550, 38.540
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 Isoform BTK-C of Tyrosine-protein kinase BTK / Agammaglobulinemia tyrosine kinase / ATK / B-cell progenitor kinase / BPK / Bruton tyrosine kinase


Mass: 31207.855 Da / Num. of mol.: 1 / Fragment: KINASE DOMAIN
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-X9S / 3-tert-butyl-N-[(1R)-6-{2-[5-methyl-1-(oxan-4-yl)-1H-pyrazol-4-yl]-3H-imidazo[4,5-b]pyridin-7-yl}-1,2,3,4-tetrahydronaphthalen-1-yl]-1,2,4-oxadiazole-5-carboxamide


Mass: 580.680 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C32H36N8O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 130 / 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: 2.33 Å3/Da / Density % sol: 47.12 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 20% PEG 3350 0.1 M Bis Tris Propane pH 7.5 0.2 M Sodium acetate trihydrate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X1A / Wavelength: 1.00003 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Mar 22, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00003 Å / Relative weight: 1
ReflectionResolution: 1.19→50 Å / Num. obs: 93292 / % possible obs: 98.9 % / Redundancy: 6.16 % / Rmerge(I) obs: 0.151 / Net I/σ(I): 7.87
Reflection shellResolution: 1.19→1.26 Å / Redundancy: 5.87 % / Rmerge(I) obs: 1.8 / Mean I/σ(I) obs: 0.4 / Num. unique obs: 93292 / % possible all: 99.1

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Processing

Software
NameVersionClassification
REFMAC5.8.0158refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
XDSdata scaling
REFMACphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1k2p

1k2p


Resolution: 1.94→38.54 Å / Cor.coef. Fo:Fc: 0.936 / Cor.coef. Fo:Fc free: 0.914 / SU B: 4.098 / SU ML: 0.115 / Cross valid method: FREE R-VALUE / σ(F): 0 / ESU R: 0.183 / ESU R Free: 0.166 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2484 1103 5 %RANDOM
Rwork0.2023 ---
obs0.2046 20939 98.83 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso max: 149.06 Å2 / Biso mean: 20.531 Å2 / Biso min: 8.5 Å2
Baniso -1Baniso -2Baniso -3
1-0.14 Å2-0 Å2-0 Å2
2---0.47 Å20 Å2
3---0.33 Å2
Refinement stepCycle: final / Resolution: 1.94→38.54 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2157 0 63 130 2350
Biso mean--31.42 24.99 -
Num. residues----265
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0192307
X-RAY DIFFRACTIONr_angle_refined_deg1.591.9623118
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.9465274
X-RAY DIFFRACTIONr_dihedral_angle_2_deg29.14724.135104
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.01515416
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.5251512
X-RAY DIFFRACTIONr_chiral_restr0.1090.2329
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0211854
LS refinement shellResolution: 1.94→1.99 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.338 79 -
Rwork0.215 1510 -
all-1589 -
obs--99.75 %

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