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- PDB-6omu: Structure of human Bruton's Tyrosine Kinase in complex with Evobr... -

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Basic information

Entry
Database: PDB / ID: 6omu
TitleStructure of human Bruton's Tyrosine Kinase in complex with Evobrutinib
ComponentsTyrosine-protein kinase BTK
KeywordsTransferase/Transferase Inhibitor / 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 phagocytosis / positive regulation of B cell proliferation / 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 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; 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-MZJ / Tyrosine-protein kinase BTK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.41 Å
AuthorsMochalkin, I. / Gardberg, A.S.
CitationJournal: J.Med.Chem. / Year: 2019
Title: Discovery of Evobrutinib: An Oral, Potent, and Highly Selective, Covalent Bruton's Tyrosine Kinase (BTK) Inhibitor for the Treatment of Immunological Diseases.
Authors: Caldwell, R.D. / Qiu, H. / Askew, B.C. / Bender, A.T. / Brugger, N. / Camps, M. / Dhanabal, M. / Dutt, V. / Eichhorn, T. / Gardberg, A.S. / Goutopoulos, A. / Grenningloh, R. / Head, J. / ...Authors: Caldwell, R.D. / Qiu, H. / Askew, B.C. / Bender, A.T. / Brugger, N. / Camps, M. / Dhanabal, M. / Dutt, V. / Eichhorn, T. / Gardberg, A.S. / Goutopoulos, A. / Grenningloh, R. / Head, J. / Healey, B. / Hodous, B.L. / Huck, B.R. / Johnson, T.L. / Jones, C. / Jones, R.C. / Mochalkin, I. / Morandi, F. / Nguyen, N. / Meyring, M. / Potnick, J.R. / Santos, D.C. / Schmidt, R. / Sherer, B. / Shutes, A. / Urbahns, K. / Follis, A.V. / Wegener, A.A. / Zimmerli, S.C. / Liu-Bujalski, L.
History
DepositionApr 19, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 14, 2019Provider: repository / Type: Initial release
Revision 1.1Sep 25, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.name
Revision 1.2Oct 11, 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)32,0633
Polymers31,5981
Non-polymers4652
Water7,710428
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)72.173, 104.520, 37.983
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
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-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#3: Chemical ChemComp-MZJ / 1-[4-({[6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl]amino}methyl)piperidin-1-yl]prop-2-en-1-one / Evobrutinib


Mass: 429.514 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H27N5O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 428 / Source method: isolated from a natural source / Formula: H2O

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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: 45.74 %
Crystal growTemperature: 295 K / Method: vapor diffusion, sitting drop
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: APS / Beamline: 22-BM / Wavelength: 1 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Feb 20, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.41→50 Å / Num. obs: 55920 / % possible obs: 99.8 % / Redundancy: 5.4 % / Rmerge(I) obs: 0.118 / Net I/σ(I): 15
Reflection shellResolution: 1.41→1.46 Å / Redundancy: 5.4 % / Rmerge(I) obs: 0.566 / Mean I/σ(I) obs: 3.5 / Num. unique obs: 5512 / % possible all: 100

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
PHASERphasing
REFMAC5.5.0066refinement
PDB_EXTRACT3.25data extraction
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5P9G

5p9g


Resolution: 1.41→22 Å / Cor.coef. Fo:Fc: 0.938 / Cor.coef. Fo:Fc free: 0.92 / SU B: 2.329 / SU ML: 0.044 / SU R Cruickshank DPI: 0.0706 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.071 / ESU R Free: 0.075
RfactorNum. reflection% reflectionSelection details
Rfree0.226 2836 5.1 %RANDOM
Rwork0.1902 ---
obs0.192 52986 99.6 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å
Displacement parametersBiso max: 63.87 Å2 / Biso mean: 10.287 Å2 / Biso min: 3.04 Å2
Baniso -1Baniso -2Baniso -3
1-0.84 Å20 Å20 Å2
2--0.11 Å20 Å2
3----0.95 Å2
Refinement stepCycle: final / Resolution: 1.41→22 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2214 0 66 428 2708
Biso mean--11.31 26.13 -
Num. residues----271
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0222426
X-RAY DIFFRACTIONr_bond_other_d00.022149
X-RAY DIFFRACTIONr_angle_refined_deg1.3911.9893284
X-RAY DIFFRACTIONr_angle_other_deg0.735017
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.1455292
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.74624.037109
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.54915436
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.5971513
X-RAY DIFFRACTIONr_chiral_restr0.080.2338
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.022722
X-RAY DIFFRACTIONr_gen_planes_other0.0040.02527
LS refinement shellResolution: 1.412→1.449 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.282 195 -
Rwork0.218 3791 -
all-3986 -
obs--98.23 %

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