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- PDB-5vfi: Bruton's tyrosine kinase (BTK) with GDC-0853 -

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Basic information

Entry
Database: PDB / ID: 5vfi
TitleBruton's tyrosine kinase (BTK) with GDC-0853
ComponentsTyrosine-protein kinase BTK
KeywordsTransferase/Transferase Inhibitor / protein 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 / histamine secretion by mast cell / positive regulation of synoviocyte proliferation ...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 / histamine secretion by mast cell / positive regulation of synoviocyte proliferation / 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) / 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 / phosphatidylinositol-3,4,5-trisphosphate binding / phospholipase binding / mesoderm development / positive regulation of immunoglobulin production / 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 / G beta:gamma signalling through BTK / Regulation of actin dynamics for phagocytic cup formation / cellular response to reactive oxygen species / positive regulation of interleukin-6 production / peptidyl-tyrosine phosphorylation / G alpha (12/13) signalling events / positive regulation of tumor necrosis factor production / DAP12 signaling / positive regulation of NF-kappaB transcription factor activity / ER-Phagosome pathway / T cell receptor signaling pathway / cytoplasmic vesicle / G alpha (q) signalling events / protein tyrosine kinase activity / Potential therapeutics for SARS / response to lipopolysaccharide / adaptive immune response / intracellular signal transduction / membrane raft / protein phosphorylation / innate immune response / perinuclear region of cytoplasm / ATP binding / identical protein binding / metal ion binding / nucleus / 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 / 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-9AJ / Tyrosine-protein kinase BTK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.59 Å
AuthorsSteinbacher, S. / Eigenbrot, C.
CitationJournal: J. Med. Chem. / Year: 2018
Title: Discovery of GDC-0853: A Potent, Selective, and Noncovalent Bruton's Tyrosine Kinase Inhibitor in Early Clinical Development.
Authors: Crawford, J.J. / Johnson, A.R. / Misner, D.L. / Belmont, L.D. / Castanedo, G. / Choy, R. / Coraggio, M. / Dong, L. / Eigenbrot, C. / Erickson, R. / Ghilardi, N. / Hau, J. / Katewa, A. / ...Authors: Crawford, J.J. / Johnson, A.R. / Misner, D.L. / Belmont, L.D. / Castanedo, G. / Choy, R. / Coraggio, M. / Dong, L. / Eigenbrot, C. / Erickson, R. / Ghilardi, N. / Hau, J. / Katewa, A. / Kohli, P.B. / Lee, W. / Lubach, J.W. / McKenzie, B.S. / Ortwine, D.F. / Schutt, L. / Tay, S. / Wei, B. / Reif, K. / Liu, L. / Wong, H. / Young, W.B.
History
DepositionApr 7, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 28, 2018Provider: repository / Type: Initial release
Revision 1.1Apr 4, 2018Group: 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 1.2Mar 13, 2024Group: Advisory / Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_unobs_or_zero_occ_atoms
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)32,95212
Polymers31,5981
Non-polymers1,35311
Water5,044280
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)72.867, 103.908, 38.464
Angle α, β, γ (deg.)90.00, 90.00, 90.00
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: UNP residues 423-693
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: BTK, AGMX1, ATK, BPK / Production host: Spodoptera (butterflies/moths)
References: UniProt: Q06187, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-9AJ / 2-[3'-(hydroxymethyl)-1-methyl-5-({5-[(2S)-2-methyl-4-(oxetan-3-yl)piperazin-1-yl]pyridin-2-yl}amino)-6-oxo[1,6-dihydro[3,4'-bipyridine]]-2'-yl]-7,7-dimethyl-3,4,7,8-tetrahydro-2H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1(6H)-one


Mass: 664.796 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C37H44N8O4
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 280 / 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: 2.3 Å3/Da / Density % sol: 46.62 %
Crystal growTemperature: 300 K / Method: vapor diffusion / pH: 6.5 / Details: PEG 5000 MME ammonium sulfate MES pH 6.5

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Data collection

DiffractionMean temperature: 110 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1.00004 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 24, 2010
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00004 Å / Relative weight: 1
ReflectionResolution: 1.59→60 Å / Num. obs: 40127 / % possible obs: 100 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 7.8 % / Biso Wilson estimate: 14.6 Å2 / Rsym value: 0.069 / Net I/σ(I): 21.2

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Processing

Software
NameVersionClassification
REFMAC5.8.0155refinement
XDSdata reduction
XSCALEdata scaling
REFMACphasing
RefinementResolution: 1.59→59.66 Å / Cor.coef. Fo:Fc: 0.956 / Cor.coef. Fo:Fc free: 0.943 / SU B: 4.174 / SU ML: 0.069 / Cross valid method: THROUGHOUT / ESU R: 0.099 / ESU R Free: 0.096 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.21576 3631 9 %RANDOM
Rwork0.18592 ---
obs0.18867 36493 99.93 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å
Displacement parametersBiso mean: 13.999 Å2
Baniso -1Baniso -2Baniso -3
1-0.15 Å20 Å20 Å2
2---0.04 Å20 Å2
3----0.11 Å2
Refinement stepCycle: 1 / Resolution: 1.59→59.66 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2214 0 91 280 2585
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0192477
X-RAY DIFFRACTIONr_bond_other_d00.022301
X-RAY DIFFRACTIONr_angle_refined_deg1.9061.9923351
X-RAY DIFFRACTIONr_angle_other_deg3.67735316
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.3345296
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.36924.035114
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.86815433
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.9591513
X-RAY DIFFRACTIONr_chiral_restr0.1050.2343
X-RAY DIFFRACTIONr_gen_planes_refined0.0120.022779
X-RAY DIFFRACTIONr_gen_planes_other0.0170.02571
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.1141.3151148
X-RAY DIFFRACTIONr_mcbond_other2.1111.311147
X-RAY DIFFRACTIONr_mcangle_it2.6232.9611456
X-RAY DIFFRACTIONr_mcangle_other2.6232.9681457
X-RAY DIFFRACTIONr_scbond_it4.2121.8931329
X-RAY DIFFRACTIONr_scbond_other4.221.8441321
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other5.0663.8211882
X-RAY DIFFRACTIONr_long_range_B_refined6.55511.5753001
X-RAY DIFFRACTIONr_long_range_B_other6.43810.5392913
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.59→1.676 Å / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.29 511 -
Rwork0.246 5272 -
obs--99.98 %
Refinement TLS params.Method: refined / Origin x: 16.5036 Å / Origin y: 15.5282 Å / Origin z: 5.8752 Å
111213212223313233
T0.007 Å20.0015 Å20.0009 Å2-0.0202 Å20.0007 Å2--0.006 Å2
L0.2172 °2-0.0666 °2-0.0057 °2-0.63 °2-0.0665 °2--0.3418 °2
S-0.0034 Å °-0.0318 Å °-0.0277 Å °0.0268 Å °0.0109 Å °0.0402 Å °0.0412 Å °-0.0003 Å °-0.0075 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A389 - 659
2X-RAY DIFFRACTION1A701

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