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- PDB-3pyy: Discovery and Characterization of a Cell-Permeable, Small-molecul... -

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Basic information

Entry
Database: PDB / ID: 3pyy
TitleDiscovery and Characterization of a Cell-Permeable, Small-molecule c-Abl Kinase Activator that Binds to the Myristoyl Binding Site
ComponentsV-abl Abelson murine leukemia viral oncogene homolog 1 isoform b variant
KeywordsTRANSFERASE / Tyrosine kinase
Function / homology
Function and homology information


: / positive regulation of actin filament binding / positive regulation of oxidoreductase activity / protein localization to cytoplasmic microtubule plus-end / DNA conformation change / podocyte apoptotic process / DN4 thymocyte differentiation / Role of ABL in ROBO-SLIT signaling / response to epinephrine / transitional one stage B cell differentiation ...: / positive regulation of actin filament binding / positive regulation of oxidoreductase activity / protein localization to cytoplasmic microtubule plus-end / DNA conformation change / podocyte apoptotic process / DN4 thymocyte differentiation / Role of ABL in ROBO-SLIT signaling / response to epinephrine / transitional one stage B cell differentiation / activation of protein kinase C activity / nicotinate-nucleotide adenylyltransferase activity / regulation of modification of synaptic structure / positive regulation of microtubule binding / delta-catenin binding / B cell proliferation involved in immune response / positive regulation of extracellular matrix organization / neuroepithelial cell differentiation / microspike assembly / positive regulation of Wnt signaling pathway, planar cell polarity pathway / cerebellum morphogenesis / positive regulation of blood vessel branching / B-1 B cell homeostasis / mitochondrial depolarization / negative regulation of ubiquitin-protein transferase activity / neuropilin signaling pathway / neuropilin binding / bubble DNA binding / negative regulation of protein serine/threonine kinase activity / activated T cell proliferation / cellular response to dopamine / regulation of cell motility / regulation of Cdc42 protein signal transduction / proline-rich region binding / positive regulation of dendrite development / mitogen-activated protein kinase binding / myoblast proliferation / alpha-beta T cell differentiation / regulation of hematopoietic stem cell differentiation / syntaxin binding / cardiac muscle cell proliferation / regulation of T cell differentiation / regulation of axon extension / HDR through Single Strand Annealing (SSA) / positive regulation of cell migration involved in sprouting angiogenesis / negative regulation of cell-cell adhesion / Fc-gamma receptor signaling pathway involved in phagocytosis / Myogenesis / regulation of microtubule polymerization / positive regulation of osteoblast proliferation / RUNX2 regulates osteoblast differentiation / platelet-derived growth factor receptor-beta signaling pathway / positive regulation of focal adhesion assembly / negative regulation of cellular senescence / Bergmann glial cell differentiation / associative learning / neuromuscular process controlling balance / regulation of endocytosis / negative regulation of BMP signaling pathway / negative regulation of mitotic cell cycle / actin monomer binding / negative regulation of long-term synaptic potentiation / endothelial cell migration / RHO GTPases Activate WASPs and WAVEs / positive regulation of T cell migration / canonical NF-kappaB signal transduction / signal transduction in response to DNA damage / negative regulation of double-strand break repair via homologous recombination / mismatch repair / BMP signaling pathway / regulation of cell adhesion / negative regulation of endothelial cell apoptotic process / four-way junction DNA binding / positive regulation of substrate adhesion-dependent cell spreading / peptidyl-tyrosine autophosphorylation / positive regulation of vasoconstriction / positive regulation of stress fiber assembly / spleen development / ruffle / cellular response to transforming growth factor beta stimulus / positive regulation of establishment of T cell polarity / ERK1 and ERK2 cascade / positive regulation of interleukin-2 production / actin filament polymerization / phosphotyrosine residue binding / SH2 domain binding / response to endoplasmic reticulum stress / ephrin receptor binding / positive regulation of endothelial cell migration / positive regulation of mitotic cell cycle / substrate adhesion-dependent cell spreading / positive regulation of release of sequestered calcium ion into cytosol / post-embryonic development / thymus development / regulation of autophagy / neural tube closure / establishment of localization in cell / integrin-mediated signaling pathway / regulation of actin cytoskeleton organization / protein kinase C binding
Similarity search - Function
Tyrosine-protein kinase ABL1/transforming protein Abl / F-actin binding / F-actin binding / F-actin binding domain (FABD) / Tyrosine-protein kinase ABL, SH2 domain / SH3 domain / SH2 domain / Src homology 2 (SH2) domain profile. / Src homology 2 domains / SH2 domain ...Tyrosine-protein kinase ABL1/transforming protein Abl / F-actin binding / F-actin binding / F-actin binding domain (FABD) / Tyrosine-protein kinase ABL, SH2 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. / 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-3YY / Chem-STI / Tyrosine-protein kinase ABL1 / Tyrosine-protein kinase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.85 Å
AuthorsYang, J. / Campobasso, N. / Biju, M.P. / Fisher, K. / Pan, X.Q. / Cottom, J. / Galbraith, S. / Ho, T. / Zhang, H. / Hong, X. ...Yang, J. / Campobasso, N. / Biju, M.P. / Fisher, K. / Pan, X.Q. / Cottom, J. / Galbraith, S. / Ho, T. / Zhang, H. / Hong, X. / Ward, P. / Hofmann, G. / Siegfried, B.
CitationJournal: Chem.Biol. / Year: 2011
Title: Discovery and Characterization of a Cell-Permeable, Small-Molecule c-Abl Kinase Activator that Binds to the Myristoyl Binding Site.
Authors: Yang, J. / Campobasso, N. / Biju, M.P. / Fisher, K. / Pan, X.Q. / Cottom, J. / Galbraith, S. / Ho, T. / Zhang, H. / Hong, X. / Ward, P. / Hofmann, G. / Siegfried, B. / Zappacosta, F. / ...Authors: Yang, J. / Campobasso, N. / Biju, M.P. / Fisher, K. / Pan, X.Q. / Cottom, J. / Galbraith, S. / Ho, T. / Zhang, H. / Hong, X. / Ward, P. / Hofmann, G. / Siegfried, B. / Zappacosta, F. / Washio, Y. / Cao, P. / Qu, J. / Bertrand, S. / Wang, D.Y. / Head, M.S. / Li, H. / Moores, S. / Lai, Z. / Johanson, K. / Burton, G. / Erickson-Miller, C. / Simpson, G. / Tummino, P. / Copeland, R.A. / Oliff, A.
History
DepositionDec 13, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 9, 2011Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Jan 24, 2018Group: Structure summary / Category: audit_author / Item: _audit_author.name
Revision 1.3Feb 21, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / struct_ref_seq_dif / struct_site
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI ..._chem_comp.pdbx_synonyms / _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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: V-abl Abelson murine leukemia viral oncogene homolog 1 isoform b variant
B: V-abl Abelson murine leukemia viral oncogene homolog 1 isoform b variant
hetero molecules


Theoretical massNumber of molelcules
Total (without water)71,87211
Polymers69,4172
Non-polymers2,4559
Water3,873215
1
A: V-abl Abelson murine leukemia viral oncogene homolog 1 isoform b variant
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,7315
Polymers34,7091
Non-polymers1,0224
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: V-abl Abelson murine leukemia viral oncogene homolog 1 isoform b variant
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,1416
Polymers34,7091
Non-polymers1,4335
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)74.391, 95.432, 115.502
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein V-abl Abelson murine leukemia viral oncogene homolog 1 isoform b variant


Mass: 34708.566 Da / Num. of mol.: 2 / Fragment: UNP residues 266-549
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q59FK4, UniProt: P00519*PLUS

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Non-polymers , 6 types, 224 molecules

#2: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-STI / 4-(4-METHYL-PIPERAZIN-1-YLMETHYL)-N-[4-METHYL-3-(4-PYRIDIN-3-YL-PYRIMIDIN-2-YLAMINO)-PHENYL]-BENZAMIDE / STI-571 / IMATINIB / Imatinib


Mass: 493.603 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C29H31N7O / Comment: medication, inhibitor*YM
#4: Chemical ChemComp-3YY / (5R)-5-[3-(4-fluorophenyl)-1-phenyl-1H-pyrazol-4-yl]imidazolidine-2,4-dione


Mass: 336.320 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H13FN4O2
#5: Chemical ChemComp-2PE / NONAETHYLENE GLYCOL / Polyethylene glycol


Mass: 414.488 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H38O10 / Comment: precipitant*YM
#6: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#7: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 215 / 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: 2.95 Å3/Da / Density % sol: 58.35 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 8
Details: 20 mgs/ml protein in 20 mM Tris-HCl, pH 8.0, 100 mM NaCl, 3 mM DTT and 5% (v/v) glycerol. Reservoir with 0.4 M ammonium phosphate. Cryo w/ 15%-30% glycerol, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-G / Wavelength: 0.97872 Å
DetectorType: RAYONIX MX-225 / Detector: CCD / Date: Feb 17, 2010
RadiationMonochromator: diamond / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97872 Å / Relative weight: 1
ReflectionResolution: 1.85→30 Å / Num. obs: 69872 / % possible obs: 99 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1

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Processing

Software
NameVersionClassification
MAR345dtbdata collection
PHASERphasing
PHENIX(phenix.refine: 1.6_289)refinement
HKL-2000data reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.85→29.963 Å / SU ML: 0.18 / σ(F): 0.03 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2039 1922 2.87 %Random
Rwork0.1886 ---
obs0.1891 66950 94.89 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 60.008 Å2 / ksol: 0.4 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1-2.378 Å20 Å2-0 Å2
2--3.617 Å2-0 Å2
3----5.995 Å2
Refinement stepCycle: LAST / Resolution: 1.85→29.963 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4223 0 173 215 4611
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0074528
X-RAY DIFFRACTIONf_angle_d1.0766125
X-RAY DIFFRACTIONf_dihedral_angle_d15.8361620
X-RAY DIFFRACTIONf_chiral_restr0.071631
X-RAY DIFFRACTIONf_plane_restr0.004803
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.85-1.89860.24451190.23493972X-RAY DIFFRACTION82
1.8986-1.94990.2461220.22154149X-RAY DIFFRACTION86
1.9499-2.00730.24411310.2044400X-RAY DIFFRACTION91
2.0073-2.0720.221320.19764482X-RAY DIFFRACTION93
2.072-2.14610.20531380.1894598X-RAY DIFFRACTION95
2.1461-2.2320.22061340.18174604X-RAY DIFFRACTION95
2.232-2.33350.221370.18824692X-RAY DIFFRACTION96
2.3335-2.45650.21391400.18714728X-RAY DIFFRACTION97
2.4565-2.61030.221400.1914772X-RAY DIFFRACTION98
2.6103-2.81170.19081420.194808X-RAY DIFFRACTION98
2.8117-3.09440.23691460.20364873X-RAY DIFFRACTION99
3.0944-3.54160.17971440.19274900X-RAY DIFFRACTION99
3.5416-4.45960.18481460.16554940X-RAY DIFFRACTION99
4.4596-29.96720.19321510.18485110X-RAY DIFFRACTION99

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