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- PDB-8tu3: Bruton's tyrosine kinase in complex with covalent inhibitor compo... -

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Basic information

Entry
Database: PDB / ID: 8tu3
TitleBruton's tyrosine kinase in complex with covalent inhibitor compound 10
ComponentsTyrosine-protein kinase BTK
KeywordsTRANSFERASE/INHIBITOR / kinase / 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 / negative regulation of B cell proliferation / Fc-epsilon receptor signaling pathway / B cell activation / 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 / apoptotic signaling pathway / FCGR3A-mediated phagocytosis / B cell receptor signaling pathway / non-specific protein-tyrosine kinase / calcium-mediated signaling / non-membrane spanning protein tyrosine kinase activity / Regulation of actin dynamics for phagocytic cup formation / G beta:gamma signalling through BTK / peptidyl-tyrosine phosphorylation / positive regulation of interleukin-6 production / cellular response to reactive oxygen species / 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 / protein tyrosine kinase activity / cytoplasmic vesicle / G alpha (q) signalling events / 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 / 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 / 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
: / Tyrosine-protein kinase BTK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / SAD / Resolution: 1.7 Å
AuthorsMetrick, C.M.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2024
Title: Discovery and Preclinical Characterization of BIIB129, a Covalent, Selective, and Brain-Penetrant BTK Inhibitor for the Treatment of Multiple Sclerosis.
Authors: Himmelbauer, M.K. / Bajrami, B. / Basile, R. / Capacci, A. / Chen, T. / Choi, C.K. / Gilfillan, R. / Gonzalez-Lopez de Turiso, F. / Gu, C. / Hoemberger, M. / Johnson, D.S. / Jones, J.H. / ...Authors: Himmelbauer, M.K. / Bajrami, B. / Basile, R. / Capacci, A. / Chen, T. / Choi, C.K. / Gilfillan, R. / Gonzalez-Lopez de Turiso, F. / Gu, C. / Hoemberger, M. / Johnson, D.S. / Jones, J.H. / Kadakia, E. / Kirkland, M. / Lin, E.Y. / Liu, Y. / Ma, B. / Magee, T. / Mantena, S. / Marx, I.E. / Metrick, C.M. / Mingueneau, M. / Murugan, P. / Muste, C.A. / Nadella, P. / Nevalainen, M. / Parker Harp, C.R. / Pattaropong, V. / Pietrasiewicz, A. / Prince, R.J. / Purgett, T.J. / Santoro, J.C. / Schulz, J. / Sciabola, S. / Tang, H. / Vandeveer, H.G. / Wang, T. / Yousaf, Z. / Helal, C.J. / Hopkins, B.T.
History
DepositionAug 15, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 26, 2024Provider: repository / Type: Initial release

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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)33,0492
Polymers32,6801
Non-polymers3681
Water1,42379
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)70.430, 104.610, 38.080
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: 32680.471 Da / Num. of mol.: 1 / Fragment: Protein kinase domain residues 382-659
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-UEO / 1-[(4R)-4-{[(6P,8S)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]oxy}azepan-1-yl]propan-1-one


Mass: 368.433 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H24N6O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 79 / 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: 2.15 Å3/Da / Density % sol: 42.69 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / Details: bis-tris pH 6.5, ammonium tartrate, PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 0.97 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: May 20, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97 Å / Relative weight: 1
ReflectionResolution: 1.7→50 Å / Num. obs: 31800 / % possible obs: 99.9 % / Redundancy: 6.4 % / Biso Wilson estimate: 20.75 Å2 / CC1/2: 0.99 / Net I/σ(I): 8.19
Reflection shellResolution: 1.7→1.8 Å / Num. unique obs: 5056 / CC1/2: 0.496

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Processing

Software
NameVersionClassification
XDSdata reduction
PHENIX1.20.1_4487refinement
PHENIXphasing
Aimlessdata scaling
RefinementMethod to determine structure: SAD / Resolution: 1.7→41.99 Å / SU ML: 0.2515 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 30.7297
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2767 1589 5 %
Rwork0.2276 30166 -
obs0.2301 31755 99.87 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 27.45 Å2
Refinement stepCycle: LAST / Resolution: 1.7→41.99 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2038 0 27 79 2144
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00622169
X-RAY DIFFRACTIONf_angle_d0.77852945
X-RAY DIFFRACTIONf_chiral_restr0.0498315
X-RAY DIFFRACTIONf_plane_restr0.0083374
X-RAY DIFFRACTIONf_dihedral_angle_d19.6498807
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.7-1.750.40591420.34752700X-RAY DIFFRACTION99.86
1.75-1.820.34321420.32012700X-RAY DIFFRACTION99.86
1.82-1.890.35531430.31252706X-RAY DIFFRACTION99.89
1.89-1.980.35251410.3252680X-RAY DIFFRACTION99.82
1.98-2.080.31011420.25422705X-RAY DIFFRACTION99.82
2.08-2.210.27711440.23452730X-RAY DIFFRACTION100
2.21-2.380.30741440.25452726X-RAY DIFFRACTION99.76
2.38-2.620.23371440.22352731X-RAY DIFFRACTION99.86
2.62-30.29671450.22812757X-RAY DIFFRACTION99.97
3-3.780.27511470.20452798X-RAY DIFFRACTION99.86
3.78-41.990.22411550.17932933X-RAY DIFFRACTION99.84

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