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- PDB-7kxl: BTK1 SOAKED WITH COMPOUND 5, Y551 IS SEQUESTERED -

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Basic information

Entry
Database: PDB / ID: 7kxl
TitleBTK1 SOAKED WITH COMPOUND 5, Y551 IS SEQUESTERED
ComponentsTyrosine-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 / phospholipase binding / cell maturation / 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 / adaptive immune response / Potential therapeutics for SARS / 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-X9J / Tyrosine-protein kinase BTK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.84 Å
AuthorsGardberg, 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

Downloads & links

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Assembly

Deposited unit
A: Tyrosine-protein kinase BTK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,0805
Polymers31,3711
Non-polymers7094
Water1,42379
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)71.820, 103.840, 38.250
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: 31371.027 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-X9J / 3-tert-butyl-N-({2-fluoro-4-[2-(1-methyl-1H-pyrazol-4-yl)-1H-imidazo[4,5-b]pyridin-7-yl]phenyl}methyl)-1,2,4-oxadiazole-5-carboxamide


Mass: 474.490 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H23FN8O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 79 / 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: 2.27 Å3/Da / Density % sol: 45.89 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 20% PEG3350, 0.1M Bis Tris Propane, pH 7.5, 0.2M 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: 1.00002 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Jan 7, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00002 Å / Relative weight: 1
ReflectionResolution: 1.84→50 Å / Num. obs: 25226 / % possible obs: 97.9 % / Redundancy: 5.65 % / Biso Wilson estimate: 27.9 Å2 / Rmerge(I) obs: 0.14 / Net I/σ(I): 9.53
Reflection shellResolution: 1.85→1.95 Å / Redundancy: 4.72 % / Rmerge(I) obs: 1.321 / Mean I/σ(I) obs: 1.23 / Num. unique obs: 25226 / % possible all: 92

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Processing

Software
NameVersionClassification
BUSTER2.11refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
XDSdata scaling
BUSTERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1k2p

1k2p


Resolution: 1.84→42.08 Å / Cor.coef. Fo:Fc: 0.9473 / Cor.coef. Fo:Fc free: 0.9379 / SU R Cruickshank DPI: 0.138 / Cross valid method: FREE R-VALUE / σ(F): 0 / SU R Blow DPI: 0.141 / SU Rfree Blow DPI: 0.128 / SU Rfree Cruickshank DPI: 0.127
RfactorNum. reflection% reflectionSelection details
Rfree0.229 1260 5 %RANDOM
Rwork0.1987 ---
obs0.2002 25184 98.38 %-
Displacement parametersBiso max: 85.98 Å2 / Biso mean: 30.22 Å2 / Biso min: 12.13 Å2
Baniso -1Baniso -2Baniso -3
1--2.5447 Å20 Å20 Å2
2--1.3932 Å20 Å2
3---1.1515 Å2
Refine analyzeLuzzati coordinate error obs: 0.249 Å
Refinement stepCycle: final / Resolution: 1.84→42.08 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2136 0 47 79 2262
Biso mean--33.74 30.59 -
Num. residues----267
LS refinement shellResolution: 1.84→1.92 Å / Rfactor Rfree error: 0 / Total num. of bins used: 13
RfactorNum. reflection% reflection
Rfree0.2922 134 5.01 %
Rwork0.2518 2539 -
all0.2538 2673 -
obs--98.38 %
Refinement TLS params.Method: refined / Origin x: -19.78 Å / Origin y: 16.3037 Å / Origin z: -13.158 Å
111213212223313233
T-0.0262 Å20.0072 Å2-0.0078 Å2-0.0342 Å20.0004 Å2---0.1246 Å2
L0.3983 °20.1535 °2-0.1619 °2-0.9401 °2-0.0102 °2--0.6589 °2
S-0.0272 Å °-0.0336 Å °-0.0328 Å °0.0187 Å °0.0314 Å °0.028 Å °0.0851 Å °0.0179 Å °-0.0042 Å °
Refinement TLS groupSelection details: { A|* }

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