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- PDB-7kxp: BTK1 SOAKED WITH COMPOUND 25 -

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Basic information

Entry
Database: PDB / ID: 7kxp
TitleBTK1 SOAKED WITH COMPOUND 25
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 / 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-X9V / Tyrosine-protein kinase BTK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.83 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

Downloads & links

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Assembly

Deposited unit
A: Tyrosine-protein kinase BTK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,4916
Polymers31,5981
Non-polymers8935
Water4,864270
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)74.327, 105.360, 39.533
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-X9V / 3-tert-butyl-N-[(1S)-6-{2-[3-methyl-1-(oxan-4-yl)-1H-pyrazol-4-yl]-1H-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.: 4 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 270 / 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: 2.45 Å3/Da / Density % sol: 49.78 %
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: 0.92819 Å
DetectorType: DECTRIS PILATUS 2M / Detector: PIXEL / Date: May 16, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.92819 Å / Relative weight: 1
ReflectionResolution: 1.59→60.73 Å / Num. obs: 42213 / % possible obs: 99 % / Redundancy: 3.64 % / Rmerge(I) obs: 0.051 / Net I/σ(I): 18.51
Reflection shellResolution: 1.59→1.69 Å / Redundancy: 3.62 % / Rmerge(I) obs: 0.748 / Mean I/σ(I) obs: 1.74 / Num. unique obs: 42213 / % possible all: 99.3

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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: 1.83→60.73 Å / Cor.coef. Fo:Fc: 0.957 / Cor.coef. Fo:Fc free: 0.931 / SU B: 5.423 / SU ML: 0.087 / Cross valid method: FREE R-VALUE / σ(F): 0 / ESU R: 0.141 / ESU R Free: 0.133 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2149 2514 9.1 %RANDOM
Rwork0.1735 ---
obs0.1772 25015 97.59 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 105.54 Å2 / Biso mean: 22.414 Å2 / Biso min: 9.04 Å2
Baniso -1Baniso -2Baniso -3
1-0.15 Å20 Å20 Å2
2--0.72 Å2-0 Å2
3----0.87 Å2
Refinement stepCycle: final / Resolution: 1.83→60.73 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2214 0 59 270 2543
Biso mean--24.58 29.98 -
Num. residues----271
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0192436
X-RAY DIFFRACTIONr_bond_other_d0.0010.022255
X-RAY DIFFRACTIONr_angle_refined_deg1.251.9863306
X-RAY DIFFRACTIONr_angle_other_deg0.76435252
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.525299
X-RAY DIFFRACTIONr_dihedral_angle_2_deg29.36724.052116
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.10415451
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.0611514
X-RAY DIFFRACTIONr_chiral_restr0.0850.2346
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.022685
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02515
LS refinement shellResolution: 1.83→1.877 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.257 182 -
Rwork0.237 1861 -
all-2043 -
obs--98.79 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.69790.03460.96312.8487-0.93481.71940.06170.1288-0.1408-0.34750.009-0.28320.29990.1398-0.07070.1772-0.02660.05390.0766-0.03280.210920.68510.9819-9.6328
23.38610.9442-0.264110.18452.62065.75340.160.10670.2363-0.0623-0.18830.55220.156-0.41250.02830.0666-0.0075-0.01050.1327-0.02980.12378.082718.5724-16.9343
31.70260.09180.02911.45120.10461.50190.00950.05720.0669-0.00790.0038-0.0591-0.08920.0171-0.01330.0145-0.0032-0.0060.0035-0.00310.086921.883426.3168-2.8772
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A389 - 481
2X-RAY DIFFRACTION1A531 - 546
3X-RAY DIFFRACTION2A547 - 560
4X-RAY DIFFRACTION3A482 - 530
5X-RAY DIFFRACTION3A561 - 659

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