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- PDB-3gen: The 1.6 A crystal structure of human bruton's tyrosine kinase bou... -

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Basic information

Entry
Database: PDB / ID: 3gen
TitleThe 1.6 A crystal structure of human bruton's tyrosine kinase bound to a pyrrolopyrimidine-containing compound
ComponentsTyrosine-protein kinase BTK
KeywordsTRANSFERASE / Bruton's tyrosine kinase / 4-Amino-5-(4-phenoxyphenyl)-5H-pyrrolo[3 / 2-d]pyrimidin-7-yl-cyclopentane / TEC-family / complex / Acetylation / ATP-binding / Cytoplasm / Disease mutation / Kinase / Membrane / Metal-binding / Nucleotide-binding / Nucleus / Phosphoprotein / Polymorphism / SH2 domain / SH3 domain / Tyrosine-protein kinase / Zinc / Zinc-finger
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-B43 / Tyrosine-protein kinase BTK
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.6 Å
AuthorsMarcotte, D.J. / Liu, Y.T. / Arduini, R.M. / Hession, C.A. / Miatkowski, K. / Wildes, C.P. / Cullen, P.F. / Hopkins, B. / Mertsching, E. / Jenkins, T.J. ...Marcotte, D.J. / Liu, Y.T. / Arduini, R.M. / Hession, C.A. / Miatkowski, K. / Wildes, C.P. / Cullen, P.F. / Hopkins, B. / Mertsching, E. / Jenkins, T.J. / Romanowski, M.J. / Baker, D.P. / Silvian, L.F.
CitationJournal: Protein Sci. / Year: 2010
Title: Structures of human Bruton's tyrosine kinase in active and inactive conformations suggest a mechanism of activation for TEC family kinases.
Authors: Marcotte, D.J. / Liu, Y.T. / Arduini, R.M. / Hession, C.A. / Miatkowski, K. / Wildes, C.P. / Cullen, P.F. / Hong, V. / Hopkins, B.T. / Mertsching, E. / Jenkins, T.J. / Romanowski, M.J. / ...Authors: Marcotte, D.J. / Liu, Y.T. / Arduini, R.M. / Hession, C.A. / Miatkowski, K. / Wildes, C.P. / Cullen, P.F. / Hong, V. / Hopkins, B.T. / Mertsching, E. / Jenkins, T.J. / Romanowski, M.J. / Baker, D.P. / Silvian, L.F.
History
DepositionFeb 25, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 19, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Sep 6, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.3Mar 13, 2024Group: Source and taxonomy / Structure summary / Category: entity / pdbx_entity_src_syn / Item: _entity.details

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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)33,0512
Polymers32,6801
Non-polymers3701
Water8,917495
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)72.497, 104.306, 38.039
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 / Bruton tyrosine kinase / Agammaglobulinaemia tyrosine kinase / ATK / B-cell progenitor kinase / BPK


Mass: 32680.471 Da / Num. of mol.: 1 / Fragment: Protein kinase, residues 382-659
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: AGMX1, ATK, BPK, BTK / Plasmid: pDEST20 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q06187, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-B43 / 4-Amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl-cyclopentane / 7-cyclopentyl-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine


Mass: 370.447 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H22N4O
Details: 4-Amino-5-(4-phenoxyphenyl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl-cyclopentane
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 495 / 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: 2.2 Å3/Da / Density % sol: 44.1 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 30% Peg MME 5000,0.2M Ammonium Sulfate, 0.1M MES pH 6.5 , VAPOR DIFFUSION, SITTING DROP, temperature 277.0K

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-D / Wavelength: 1.54 Å
DetectorType: RIGAKU / Detector: IMAGE PLATE / Date: Feb 1, 2008 / Details: Varimax HR optics
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 1.6→24.5 Å / Num. obs: 38206 / % possible obs: 98.1 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Redundancy: 3.8 % / Rmerge(I) obs: 0.08
Reflection shellResolution: 1.6→1.66 Å / Redundancy: 4.1 % / Rmerge(I) obs: 0.363 / % possible all: 98.5

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Processing

Software
NameVersionClassification
HKL-2000data collection
MOLREPphasing
REFMAC5.2.0019refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1K2P

1k2p


Resolution: 1.6→21.93 Å / Cor.coef. Fo:Fc: 0.958 / Cor.coef. Fo:Fc free: 0.943 / SU B: 4.281 / SU ML: 0.068 / Cross valid method: THROUGHOUT / ESU R: 0.148 / ESU R Free: 0.103 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.23168 1915 5 %RANDOM
Rwork0.19261 ---
obs0.1946 36291 98.13 %-
all-36293 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 28.639 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0 Å20 Å2
3----0.01 Å2
Refine analyzeLuzzati coordinate error obs: 0.246 Å
Refinement stepCycle: LAST / Resolution: 1.6→21.93 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2161 0 28 495 2684
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0222247
X-RAY DIFFRACTIONr_bond_other_d0.0030.0222
X-RAY DIFFRACTIONr_angle_refined_deg1.1451.9753038
X-RAY DIFFRACTIONr_angle_other_deg1.265348
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.4715270
X-RAY DIFFRACTIONr_dihedral_angle_2_deg29.9723.846104
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.91115402
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.0411513
X-RAY DIFFRACTIONr_chiral_restr0.0810.2319
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.021697
X-RAY DIFFRACTIONr_gen_planes_other0.0030.0215
X-RAY DIFFRACTIONr_nbd_refined0.2180.21283
X-RAY DIFFRACTIONr_nbd_other0.2970.227
X-RAY DIFFRACTIONr_nbtor_refined0.3090.21529
X-RAY DIFFRACTIONr_nbtor_other0.0890.22
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1860.2461
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1980.260
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1570.249
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.9771.51372
X-RAY DIFFRACTIONr_mcbond_other2.8761.57
X-RAY DIFFRACTIONr_mcangle_it1.17922141
X-RAY DIFFRACTIONr_scbond_it1.73931027
X-RAY DIFFRACTIONr_scangle_it2.394.5894
X-RAY DIFFRACTIONr_rigid_bond_restr1.66132453
X-RAY DIFFRACTIONr_sphericity_free1.6773495
X-RAY DIFFRACTIONr_sphericity_bonded1.57732211
LS refinement shellResolution: 1.6→1.641 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.308 146 -
Rwork0.258 2680 -
obs--99.12 %

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