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- PDB-6w07: Bruton's tyrosine kinase in complex with compound 1 -

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Basic information

Entry
Database: PDB / ID: 6w07
TitleBruton's tyrosine kinase in complex with compound 1
ComponentsTyrosine-protein kinase BTK
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / kinase / transferase / 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-S9A / Tyrosine-protein kinase BTK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.51 Å
AuthorsMetrick, C.M. / Marcotte, D.J.
CitationJournal: J.Med.Chem. / Year: 2020
Title: Discovery of BIIB068: A Selective, Potent, Reversible Bruton's Tyrosine Kinase Inhibitor as an Orally Efficacious Agent for Autoimmune Diseases.
Authors: Ma, B. / Bohnert, T. / Otipoby, K.L. / Tien, E. / Arefayene, M. / Bai, J. / Bajrami, B. / Bame, E. / Chan, T.R. / Humora, M. / MacPhee, J.M. / Marcotte, D. / Mehta, D. / Metrick, C.M. / ...Authors: Ma, B. / Bohnert, T. / Otipoby, K.L. / Tien, E. / Arefayene, M. / Bai, J. / Bajrami, B. / Bame, E. / Chan, T.R. / Humora, M. / MacPhee, J.M. / Marcotte, D. / Mehta, D. / Metrick, C.M. / Moniz, G. / Polack, E. / Poreci, U. / Prefontaine, A. / Sheikh, S. / Schroeder, P. / Smirnakis, K. / Zhang, L. / Zheng, F. / Hopkins, B.T.
History
DepositionFeb 29, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 16, 2020Provider: repository / Type: Initial release
Revision 1.1Oct 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

Downloads & links

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Assembly

Deposited unit
A: Tyrosine-protein kinase BTK
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,4113
Polymers33,8971
Non-polymers5142
Water4,720262
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)71.658, 103.895, 38.230
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP21212
Space group name HallP22ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x+1/2,y+1/2,-z
#4: -x,-y,z

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Components

#1: Protein Tyrosine-protein kinase BTK / Agammaglobulinemia tyrosine kinase / ATK / B-cell progenitor kinase / BPK / Bruton tyrosine kinase


Mass: 33896.859 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: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q06187, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-S9A / ~{N}-[[2-methyl-4-[2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]phenyl]methyl]-3-propan-2-yloxy-azetidine-1-carboxamide


Mass: 435.522 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H29N7O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 262 / 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: 2.08 Å3/Da / Density % sol: 40.93 %
Crystal growTemperature: 277 K / Method: vapor diffusion / Details: bis-tris, ammonium salt, PEG

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 31-ID / Wavelength: 1 Å
DetectorType: RAYONIX MX-225 / Detector: CCD / Date: Nov 8, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.51→18.8 Å / Num. obs: 43516 / % possible obs: 95.7 % / Redundancy: 5.6 % / Biso Wilson estimate: 11.85 Å2 / Rmerge(I) obs: 0.098 / Net I/σ(I): 9.8
Reflection shellResolution: 1.51→1.59 Å / Rmerge(I) obs: 0.804 / Mean I/σ(I) obs: 1.9 / Num. unique obs: 5705 / % possible all: 86.9

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Processing

Software
NameVersionClassification
PHENIX1.17.1_3660refinement
HKL-2000data reduction
SCALAdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1K2P

1k2p


Resolution: 1.51→18.8 Å / SU ML: 0.184 / Cross valid method: FREE R-VALUE / σ(F): 0 / Phase error: 24.6774
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2671 2208 5.08 %
Rwork0.2292 41255 -
obs0.2311 43463 95.43 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 15.44 Å2
Refinement stepCycle: LAST / Resolution: 1.51→18.8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2084 0 32 270 2386
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00952180
X-RAY DIFFRACTIONf_angle_d1.19952950
X-RAY DIFFRACTIONf_chiral_restr0.0676319
X-RAY DIFFRACTIONf_plane_restr0.0069371
X-RAY DIFFRACTIONf_dihedral_angle_d20.8428802
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.51-1.540.26381270.20152245X-RAY DIFFRACTION85.08
1.54-1.580.25191390.18992342X-RAY DIFFRACTION87.45
1.58-1.620.25641230.19252339X-RAY DIFFRACTION88.78
1.62-1.660.24341160.21932447X-RAY DIFFRACTION90.12
1.66-1.710.29251450.22842469X-RAY DIFFRACTION93.59
1.71-1.770.28911460.23132484X-RAY DIFFRACTION94.43
1.77-1.830.27291340.23892595X-RAY DIFFRACTION95.99
1.83-1.90.25181210.24142634X-RAY DIFFRACTION97.66
1.9-1.990.32911730.24422595X-RAY DIFFRACTION98.26
1.99-2.10.28811330.25032674X-RAY DIFFRACTION99.12
2.1-2.230.28481420.2512676X-RAY DIFFRACTION99.37
2.23-2.40.30311500.25292699X-RAY DIFFRACTION99.65
2.4-2.640.27371410.25332712X-RAY DIFFRACTION99.83
2.64-3.020.2511590.24032721X-RAY DIFFRACTION99.97
3.02-3.80.26371300.21382783X-RAY DIFFRACTION100
3.8-18.80.21831290.2042840X-RAY DIFFRACTION96.96

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