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- PDB-1ony: Oxalyl-Aryl-Amino Benzoic Acid inhibitors of PTP1B, compound 17 -

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Basic information

Entry
Database: PDB / ID: 1ony
TitleOxalyl-Aryl-Amino Benzoic Acid inhibitors of PTP1B, compound 17
ComponentsProtein-tyrosine phosphatase, non-receptor type 1
KeywordsHYDROLASE / Protein Tyrosine Phosphatase / oxalyl-aryl-amino benzoic acid inhibitor
Function / homology
Function and homology information


regulation of hepatocyte growth factor receptor signaling pathway / PTK6 Down-Regulation / peptidyl-tyrosine dephosphorylation involved in inactivation of protein kinase activity / positive regulation of receptor catabolic process / insulin receptor recycling / negative regulation of PERK-mediated unfolded protein response / negative regulation of vascular endothelial growth factor receptor signaling pathway / regulation of intracellular protein transport / IRE1-mediated unfolded protein response / cytoplasmic side of endoplasmic reticulum membrane ...regulation of hepatocyte growth factor receptor signaling pathway / PTK6 Down-Regulation / peptidyl-tyrosine dephosphorylation involved in inactivation of protein kinase activity / positive regulation of receptor catabolic process / insulin receptor recycling / negative regulation of PERK-mediated unfolded protein response / negative regulation of vascular endothelial growth factor receptor signaling pathway / regulation of intracellular protein transport / IRE1-mediated unfolded protein response / cytoplasmic side of endoplasmic reticulum membrane / sorting endosome / mitochondrial crista / platelet-derived growth factor receptor-beta signaling pathway / positive regulation of IRE1-mediated unfolded protein response / regulation of type I interferon-mediated signaling pathway / regulation of endocytosis / non-membrane spanning protein tyrosine phosphatase activity / peptidyl-tyrosine dephosphorylation / Regulation of IFNA/IFNB signaling / regulation of signal transduction / cellular response to unfolded protein / positive regulation of protein tyrosine kinase activity / growth hormone receptor signaling pathway via JAK-STAT / negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway / negative regulation of signal transduction / Regulation of IFNG signaling / MECP2 regulates neuronal receptors and channels / endoplasmic reticulum unfolded protein response / Growth hormone receptor signaling / positive regulation of JUN kinase activity / negative regulation of insulin receptor signaling pathway / Insulin receptor recycling / ephrin receptor binding / Integrin signaling / protein dephosphorylation / negative regulation of MAP kinase activity / protein-tyrosine-phosphatase / protein phosphatase 2A binding / protein tyrosine phosphatase activity / endosome lumen / insulin receptor binding / Negative regulation of MET activity / negative regulation of ERK1 and ERK2 cascade / receptor tyrosine kinase binding / insulin receptor signaling pathway / actin cytoskeleton organization / early endosome / mitochondrial matrix / cadherin binding / protein kinase binding / enzyme binding / endoplasmic reticulum / protein-containing complex / RNA binding / zinc ion binding / cytosol / cytoplasm
Similarity search - Function
Protein-tyrosine phosphatase, non-receptor type-1/2 / Protein tyrosine phosphatase superfamily / Protein-Tyrosine Phosphatase; Chain A / Protein tyrosine phosphatase, catalytic domain / PTP type protein phosphatase domain profile. / Protein-tyrosine phosphatase / Tyrosine-specific protein phosphatase, PTPase domain / Protein-tyrosine phosphatase, catalytic / Protein tyrosine phosphatase, catalytic domain motif / Tyrosine specific protein phosphatases active site. ...Protein-tyrosine phosphatase, non-receptor type-1/2 / Protein tyrosine phosphatase superfamily / Protein-Tyrosine Phosphatase; Chain A / Protein tyrosine phosphatase, catalytic domain / PTP type protein phosphatase domain profile. / Protein-tyrosine phosphatase / Tyrosine-specific protein phosphatase, PTPase domain / Protein-tyrosine phosphatase, catalytic / Protein tyrosine phosphatase, catalytic domain motif / Tyrosine specific protein phosphatases active site. / Protein-tyrosine phosphatase, active site / Tyrosine-specific protein phosphatases domain / Tyrosine specific protein phosphatases domain profile. / Protein-tyrosine phosphatase-like / Alpha-Beta Complex / Alpha Beta
Similarity search - Domain/homology
Chem-588 / Tyrosine-protein phosphatase non-receptor type 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.15 Å
AuthorsLiu, G. / Szczepankiewicz, B.G. / Pei, Z. / Janowich, D.A. / Xin, Z. / Hadjuk, P.J. / Abad-Zapatero, C. / Liang, H. / Hutchins, C.W. / Fesik, S.W. ...Liu, G. / Szczepankiewicz, B.G. / Pei, Z. / Janowich, D.A. / Xin, Z. / Hadjuk, P.J. / Abad-Zapatero, C. / Liang, H. / Hutchins, C.W. / Fesik, S.W. / Ballaron, S.J. / Stashko, M.A. / Lubben, T. / Mika, A.K. / Zinker, B.A. / Trevillyan, J.M. / Jirousek, M.R.
Citation
Journal: J.Med.Chem. / Year: 2003
Title: Discovery and Structure-Activity Relationship of Oxalylarylaminobenzoic Acids as Inhibitors of Protein Tyrosine Phosphatase 1B
Authors: Liu, G. / Szczepankiewicz, B.G. / Pei, Z. / Janowich, D.A. / Xin, Z. / Hadjuk, P.J. / Abad-Zapatero, C. / Liang, H. / Hutchins, C.W. / Fesik, S.W. / Ballaron, S.J. / Stashko, M.A. / Lubben, ...Authors: Liu, G. / Szczepankiewicz, B.G. / Pei, Z. / Janowich, D.A. / Xin, Z. / Hadjuk, P.J. / Abad-Zapatero, C. / Liang, H. / Hutchins, C.W. / Fesik, S.W. / Ballaron, S.J. / Stashko, M.A. / Lubben, T. / Mika, A.K. / Zinker, B.A. / Trevillyan, J.M. / Jirousek, M.R.
#1: Journal: BIOORG.MED.CHEM.LETT. / Year: 2003
Title: Potent, Selective Inhibitors of Protein Tyrosine Phosphatase 1B
Authors: Xin, Z. / Oost, T.K. / Abad-Zapatero, C. / Hajduk, P.J. / Pei, Z. / Szczepankiewicz, B.G. / Hutchins, C.W. / Ballaron, S.J. / Stashko, M.A. / Lubben, T. / Trevillyan, J.M. / Jirousek, M.R. / Liu, G.
#2: Journal: J.Am.Chem.Soc. / Year: 2003
Title: Potent, Selective Protein Tyrosine Phosphatase 1B Inhibitor Using a Linked-Fragment Strategy
Authors: Szczepankiewicz, B.G. / Liu, G. / Hajduk, P.J. / Abad-Zapatero, C. / Pei, Z. / Xin, Z. / Lubben, T. / Trevillyan, J.M. / Stashko, M.A. / Ballaron, S.J. / Liang, H. / Huang, F. / Hutchins, C. ...Authors: Szczepankiewicz, B.G. / Liu, G. / Hajduk, P.J. / Abad-Zapatero, C. / Pei, Z. / Xin, Z. / Lubben, T. / Trevillyan, J.M. / Stashko, M.A. / Ballaron, S.J. / Liang, H. / Huang, F. / Hutchins, C.W. / Fesik, S.W. / Jirousek, M.R.
History
DepositionMar 2, 2003Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 20, 2003Provider: repository / Type: Initial release
Revision 1.1Apr 29, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Oct 11, 2017Group: Refinement description / Category: software / Item: _software.classification / _software.name
Revision 1.4Aug 16, 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_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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: Protein-tyrosine phosphatase, non-receptor type 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,9542
Polymers37,3661
Non-polymers5891
Water5,621312
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)89.015, 89.015, 105.352
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number152
Space group name H-MP3121

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Components

#1: Protein Protein-tyrosine phosphatase, non-receptor type 1 / Protein-tyrosine phosphatase 1B / PTP-1B


Mass: 37365.637 Da / Num. of mol.: 1 / Fragment: PTP1B Catalytic domain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PTPN1 OR PTP1B / Plasmid: pT7-7 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(D33)/pTPASE 1B / References: UniProt: P18031, protein-tyrosine-phosphatase
#2: Chemical ChemComp-588 / 2-{[2-(2-CARBAMOYL-VINYL)-4-(2-METHANESULFONYLAMINO-2-PENTYLCARBAMOYL-ETHYL)-PHENYL]-OXALYL-AMINO}-BENZOIC ACID / COMPOUND 17


Mass: 588.629 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H32N4O9S
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 312 / 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: 3.22 Å3/Da / Density % sol: 61.83 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7.1
Details: Precipitation buffer: 100 mM Hepes, 0.2 M Magnesium Acetate, 14% PEG8000, pH 7.1, VAPOR DIFFUSION, HANGING DROP, temperature 277K
Crystal grow
*PLUS
Temperature: 4 ℃ / pH: 7.5
Details: Puius, Y.A., (1997) Proc.Natl.Acad.Sci.USA, 94, 13420.
Components of the solutions
*PLUS
IDConc.Common nameCrystal-IDSol-IDChemical formula
15 mg/mlprotein1drop
25 mMTris-HCl1drop
312.5 mM1dropNaCl
40.1 mMEDTA1drop
51.5 mMdithiothreitol1drop
61.7 mMBPPM1drop
70.05 mMHEPES1drop
80.1 Mmagnesium acetate1drop
96-7 %(w/v)PEG80001drop
100.1 mMHEPES1reservoir
110.2 Mmagnesium acetate1reservoir
1212-14 %(w/v)PEG80001reservoir

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RU300 / Wavelength: 1.5418 Å
DetectorType: MARRESEARCH / Detector: CCD / Date: Aug 1, 2000 / Details: mirrors
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2→50 Å / Num. all: 32536 / Num. obs: 30332 / % possible obs: 81.3 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 1 / Redundancy: 4.8 % / Biso Wilson estimate: 33.3 Å2 / Rmerge(I) obs: 0.065 / Rsym value: 0.065 / Net I/σ(I): 16.9
Reflection shellResolution: 2→2.07 Å / Redundancy: 4.1 % / Rmerge(I) obs: 0.571 / Mean I/σ(I) obs: 2.1 / Num. unique all: 3152 / Rsym value: 0.571 / % possible all: 96.5

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Processing

Software
NameVersionClassification
CNX2000refinement
MAR345data collection
HKL-2000data scaling
CNX2000phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 1TYR and initial internal refinement

1tyr


Resolution: 2.15→17.44 Å / Rfactor Rfree error: 0.005 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 2 / σ(I): 0 / Stereochemistry target values: Engh & Huber
Details: Residue CYS215, listed in remark 500, corresponds to the active site CYS which is known to be in a strained conformation in this class of enzymes. Strained conformation of Gly259 is caused ...Details: Residue CYS215, listed in remark 500, corresponds to the active site CYS which is known to be in a strained conformation in this class of enzymes. Strained conformation of Gly259 is caused by the presence of the inhibitor in the active site and in the vicinity of Gln262.
RfactorNum. reflection% reflectionSelection details
Rfree0.22 2308 10 %RANDOM
Rwork0.194 ---
all0.206 26709 --
obs0.206 23083 86.5 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 73.0446 Å2 / ksol: 0.388378 e/Å3
Displacement parametersBiso mean: 36.2 Å2
Baniso -1Baniso -2Baniso -3
1-3.25 Å24.54 Å20 Å2
2--3.25 Å20 Å2
3----6.5 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.27 Å0.28 Å
Luzzati d res low-6 Å
Luzzati sigma a0.18 Å0.18 Å
Refinement stepCycle: LAST / Resolution: 2.15→17.44 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2301 0 41 312 2654
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.007
X-RAY DIFFRACTIONc_angle_deg1.3
X-RAY DIFFRACTIONc_dihedral_angle_d22.7
X-RAY DIFFRACTIONc_improper_angle_d0.72
X-RAY DIFFRACTIONc_mcbond_it1.661.5
X-RAY DIFFRACTIONc_mcangle_it2.612
X-RAY DIFFRACTIONc_scbond_it2.632
X-RAY DIFFRACTIONc_scangle_it3.862.5
LS refinement shellResolution: 2.15→2.23 Å / Rfactor Rfree error: 0.017 / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.241 208 11.3 %
Rwork0.209 1637 -
obs-2899 69.8 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PARAMPROTEIN.TOP
X-RAY DIFFRACTION2588.PAR588.TOP
Refinement
*PLUS
Rfactor Rfree: 0.22
Solvent computation
*PLUS
Displacement parameters
*PLUS
Refine LS restraints
*PLUS
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_dihedral_angle_d
X-RAY DIFFRACTIONc_dihedral_angle_deg22.7
X-RAY DIFFRACTIONc_improper_angle_d
X-RAY DIFFRACTIONc_improper_angle_deg0.72

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