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- PDB-7r61: BTK in complex with 25A -

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Basic information

Entry
Database: PDB / ID: 7r61
TitleBTK in complex with 25A
ComponentsTyrosine-protein kinase BTK
KeywordsTRANSFERASE/INHIBITOR / Kinase / Kinase inhibitor / 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 / B cell activation / negative regulation of B cell proliferation / Fc-epsilon receptor signaling pathway / mesoderm development / phosphatidylinositol-3,4,5-trisphosphate binding / phospholipase binding / RHO GTPases Activate WASPs and WAVEs / positive regulation of B cell proliferation / positive regulation of phagocytosis / cell maturation / FCERI mediated Ca+2 mobilization / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / calcium-mediated signaling / apoptotic signaling pathway / FCGR3A-mediated phagocytosis / B cell receptor signaling pathway / non-specific protein-tyrosine kinase / non-membrane spanning protein tyrosine kinase activity / Regulation of actin dynamics for phagocytic cup formation / G beta:gamma signalling through BTK / cellular response to reactive oxygen species / peptidyl-tyrosine phosphorylation / positive regulation of interleukin-6 production / 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 / G alpha (q) signalling events / protein tyrosine kinase activity / 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 / 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 / SH3 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 / Protein tyrosine and serine/threonine kinase / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily
Similarity search - Domain/homology
Chem-2IJ / Tyrosine-protein kinase BTK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.52 Å
AuthorsGardberg, A.
CitationJournal: Chemmedchem / Year: 2021
Title: Discovery of Covalent Bruton's Tyrosine Kinase Inhibitors with Decreased CYP2C8 Inhibitory Activity.
Authors: Qiu, H. / Ali, Z. / Bowlan, J. / Caldwell, R. / Gardberg, A. / Glaser, N. / Goutopoulos, A. / Head, J. / Johnson, T. / Maurer, C. / Georgi, K. / Grenningloh, R. / Fang, Z. / Morandi, F. / ...Authors: Qiu, H. / Ali, Z. / Bowlan, J. / Caldwell, R. / Gardberg, A. / Glaser, N. / Goutopoulos, A. / Head, J. / Johnson, T. / Maurer, C. / Georgi, K. / Grenningloh, R. / Fang, Z. / Morandi, F. / Rohdich, F. / Schmidt, R. / Follis, A.V. / Sherer, B.
History
DepositionJun 22, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 6, 2021Provider: repository / Type: Initial release
Revision 1.1Oct 20, 2021Group: Database references / Category: citation / citation_author / Item: _citation.title
Revision 1.2Dec 29, 2021Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)32,1144
Polymers31,5411
Non-polymers5733
Water1,892105
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area400 Å2
ΔGint4 kcal/mol
Surface area12980 Å2
Unit cell
Length a, b, c (Å)70.646, 104.076, 38.090
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: 31541.236 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: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q06187, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-2IJ / 5-{(3S)-1-[(Z)-iminomethyl]piperidin-3-yl}-2-(4-phenoxyphenoxy)pyridine-3-carboxamide


Mass: 416.472 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H24N4O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 105 / 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: 2.24 Å3/Da / Density % sol: 45.19 %
Crystal growTemperature: 295 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: SLS / Beamline: X06DA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Apr 29, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.52→50 Å / Num. obs: 44018 / % possible obs: 99 % / Redundancy: 6.02 % / Rmerge(I) obs: 0.102 / Net I/σ(I): 10.61
Reflection shellResolution: 1.52→1.61 Å / Redundancy: 5.77 % / Rmerge(I) obs: 1.8 / Mean I/σ(I) obs: 0.87 / Num. unique obs: 6697 / % possible all: 94.9

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
Aimlessdata scaling
PHASERphasing
REFMAC5.8.0049refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1k2p

1k2p


Resolution: 1.52→38.09 Å / Cor.coef. Fo:Fc: 0.961 / Cor.coef. Fo:Fc free: 0.95 / SU B: 5.617 / SU ML: 0.091 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.086 / ESU R Free: 0.087 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : RESIDUAL ONLY
RfactorNum. reflection% reflectionSelection details
Rfree0.241 2201 5 %RANDOM
Rwork0.2089 ---
obs0.2105 41815 99.03 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 87.88 Å2 / Biso mean: 21.268 Å2 / Biso min: 8.54 Å2
Refinement stepCycle: final / Resolution: 1.52→38.09 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2109 0 39 105 2253
Biso mean--30.72 29.31 -
Num. residues----266
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0192244
X-RAY DIFFRACTIONr_bond_other_d0.0020.022057
X-RAY DIFFRACTIONr_angle_refined_deg1.6821.9773042
X-RAY DIFFRACTIONr_angle_other_deg0.9134721
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.3915273
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.24923.50597
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.8915375
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.311512
X-RAY DIFFRACTIONr_chiral_restr0.1170.2325
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.022527
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02529
LS refinement shellResolution: 1.52→1.555 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.43 142 -
Rwork0.412 2694 -
obs--88.76 %

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