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

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Basic information

Entry
Database: PDB / ID: 7kxm
TitleBTK1 SOAKED WITH COMPOUND 5, Y551 IS SEQUESTERED
ComponentsTyrosine-protein kinase BTK
KeywordsTRANSFERASE / PROTEIN KINASE
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 / B cell receptor signaling pathway / cellular response to reactive oxygen species / non-membrane spanning protein tyrosine kinase activity / FCGR3A-mediated phagocytosis / non-specific protein-tyrosine kinase / apoptotic signaling pathway / calcium-mediated signaling / : / Regulation of actin dynamics for phagocytic cup formation / positive regulation of interleukin-6 production / positive regulation of tumor necrosis factor production / G beta:gamma signalling through BTK / DAP12 signaling / G alpha (12/13) signalling events / T cell receptor signaling pathway / ER-Phagosome pathway / protein tyrosine kinase activity / cytoplasmic vesicle / 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 / 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 / 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-X9M / Tyrosine-protein kinase BTK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.33 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

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Assembly

Deposited unit
A: Tyrosine-protein kinase BTK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,1722
Polymers31,5981
Non-polymers5741
Water3,099172
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area13140 Å2
MethodPISA
Unit cell
Length a, b, c (Å)72.194, 104.344, 38.365
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 / 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-X9M / 4-tert-butyl-N-(2-methyl-3-{2-[4-(morpholine-4-carbonyl)phenyl]-1H-imidazo[4,5-b]pyridin-7-yl}phenyl)benzamide


Mass: 573.684 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C35H35N5O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 172 / 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: 2.29 Å3/Da / Density % sol: 46.21 %
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 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: Aug 21, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.33→50 Å / Num. obs: 67021 / % possible obs: 99.3 % / Redundancy: 5.82 % / Biso Wilson estimate: 19.25 Å2 / Rmerge(I) obs: 0.059 / Net I/σ(I): 14.62
Reflection shellResolution: 1.33→1.41 Å / Redundancy: 4.9 % / Rmerge(I) obs: 1.45 / Mean I/σ(I) obs: 0.87 / Num. unique obs: 67021 / % possible all: 96.4

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Processing

Software
NameVersionClassification
BUSTER2.11.5refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
XDSdata scaling
BUSTERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1k2p

1k2p


Resolution: 1.33→42.29 Å / Cor.coef. Fo:Fc: 0.9524 / Cor.coef. Fo:Fc free: 0.819 / SU R Cruickshank DPI: 0.055 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.057 / SU Rfree Blow DPI: 0.064 / SU Rfree Cruickshank DPI: 0.063
RfactorNum. reflection% reflectionSelection details
Rfree0.247 3351 5 %RANDOM
Rwork0.2008 ---
obs0.2032 67019 99.33 %-
Displacement parametersBiso max: 116.31 Å2 / Biso mean: 24.45 Å2 / Biso min: 10.14 Å2
Baniso -1Baniso -2Baniso -3
1--2.1361 Å20 Å20 Å2
2--0.5826 Å20 Å2
3---1.5535 Å2
Refine analyzeLuzzati coordinate error obs: 0.18 Å
Refinement stepCycle: final / Resolution: 1.33→42.29 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2174 0 43 172 2389
Biso mean--21.28 28.95 -
Num. residues----271
LS refinement shellResolution: 1.33→1.36 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2628 230 5 %
Rwork0.2512 4371 -
all0.2518 4601 -
obs--99.33 %
Refinement TLS params.Method: refined / Origin x: 16.1393 Å / Origin y: 16.3014 Å / Origin z: 6.033 Å
111213212223313233
T-0.0339 Å20.0041 Å2-0.0045 Å2--0.0602 Å20 Å2---0.0086 Å2
L0.383 °20.1027 °2-0.1884 °2-0.7211 °2-0.1256 °2--0.8024 °2
S-0.0118 Å °-0.0415 Å °-0.0381 Å °0.0009 Å °0.0217 Å °0.0439 Å °0.0864 Å °0.0448 Å °-0.0099 Å °
Refinement TLS groupSelection details: { A|* }

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