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- PDB-1onz: Oxalyl-aryl-Amino Benzoic acid Inhibitors of PTP1B, compound 8b -

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Basic information

Entry
Database: PDB / ID: 1onz
TitleOxalyl-aryl-Amino Benzoic acid Inhibitors of PTP1B, compound 8b
ComponentsProtein-tyrosine phosphatase, non-receptor type 1
KeywordsHYDROLASE / Protein Tyrosine Phosphatase / oxalyl-aryl-benzoic acid compound with napthyl moiety anchor inhibitor
Function / homology
Function and homology information


PTK6 Down-Regulation / regulation of hepatocyte growth factor receptor signaling pathway / positive regulation of receptor catabolic process / insulin receptor recycling / negative regulation of vascular endothelial growth factor receptor signaling pathway / regulation of intracellular protein transport / positive regulation of protein tyrosine kinase activity / IRE1-mediated unfolded protein response / mitochondrial crista / platelet-derived growth factor receptor-beta signaling pathway ...PTK6 Down-Regulation / regulation of hepatocyte growth factor receptor signaling pathway / positive regulation of receptor catabolic process / insulin receptor recycling / negative regulation of vascular endothelial growth factor receptor signaling pathway / regulation of intracellular protein transport / positive regulation of protein tyrosine kinase activity / IRE1-mediated unfolded protein response / mitochondrial crista / platelet-derived growth factor receptor-beta signaling pathway / sorting endosome / cytoplasmic side of endoplasmic reticulum membrane / negative regulation of vascular associated smooth muscle cell migration / positive regulation of IRE1-mediated unfolded protein response / regulation of type I interferon-mediated signaling pathway / negative regulation of PERK-mediated unfolded protein response / positive regulation of systemic arterial blood pressure / vascular endothelial cell response to oscillatory fluid shear stress / regulation of endocytosis / Regulation of IFNA/IFNB signaling / peptidyl-tyrosine dephosphorylation / regulation of postsynapse assembly / regulation of proteolysis / positive regulation of JUN kinase activity / cellular response to fibroblast growth factor stimulus / growth hormone receptor signaling pathway via JAK-STAT / cellular response to angiotensin / positive regulation of endothelial cell apoptotic process / negative regulation of cell-substrate adhesion / negative regulation of MAP kinase activity / cellular response to unfolded protein / regulation of signal transduction / negative regulation of signal transduction / Regulation of IFNG signaling / Growth hormone receptor signaling / positive regulation of heart rate / negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway / endoplasmic reticulum unfolded protein response / positive regulation of cardiac muscle cell apoptotic process / MECP2 regulates neuronal receptors and channels / protein dephosphorylation / Insulin receptor recycling / cellular response to platelet-derived growth factor stimulus / ephrin receptor binding / Integrin signaling / protein tyrosine phosphatase activity / protein-tyrosine-phosphatase / protein tyrosine phosphatase activity, metal-dependent / histone H2AXY142 phosphatase activity / non-membrane spanning protein tyrosine phosphatase activity / negative regulation of insulin receptor signaling pathway / cellular response to nitric oxide / negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / protein phosphatase 2A binding / Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells / endosome lumen / insulin receptor binding / cellular response to nerve growth factor stimulus / response to nutrient levels / negative regulation of ERK1 and ERK2 cascade / Negative regulation of MET activity / receptor tyrosine kinase binding / insulin receptor signaling pathway / negative regulation of neuron projection development / actin cytoskeleton organization / cellular response to hypoxia / early endosome / postsynapse / mitochondrial matrix / cadherin binding / negative regulation of cell population proliferation / protein kinase binding / glutamatergic synapse / 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 ...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-968 / Tyrosine-protein phosphatase non-receptor type 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.4 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)37,7172
Polymers37,3661
Non-polymers3511
Water5,026279
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)88.614, 88.614, 105.167
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-968 / 2-[(7-HYDROXY-NAPHTHALEN-1-YL)-OXALYL-AMINO]-BENZOIC ACID / COMPOUND 8B


Mass: 351.310 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H13NO6
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 279 / 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: 3.19 Å3/Da / Density % sol: 61.42 %
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 RU200 / Wavelength: 1.5418 Å
DetectorType: MARRESEARCH / Detector: CCD / Date: Mar 4, 2000 / Details: mirrors
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.2→20 Å / Num. all: 24913 / Num. obs: 23620 / % possible obs: 94.8 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 1 / Redundancy: 4.4 % / Biso Wilson estimate: 42.8 Å2 / Rmerge(I) obs: 0.046 / Rsym value: 0.046 / Net I/σ(I): 13.2
Reflection shellResolution: 2.2→2.28 Å / Redundancy: 4.5 % / Rmerge(I) obs: 0.266 / Mean I/σ(I) obs: 2.4 / Num. unique all: 2448 / Rsym value: 0.266 / % possible all: 95.2

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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 of other complexes

1tyr


Resolution: 2.4→19.73 Å / Rfactor Rfree error: 0.005 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 2 / σ(I): 0
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.
RfactorNum. reflection% reflectionSelection details
Rfree0.223 1651 10 %RANDOM
Rwork0.193 ---
all0.229 18495 --
obs0.226 16513 86.4 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 45.3196 Å2 / ksol: 0.336596 e/Å3
Displacement parametersBiso mean: 45.1 Å2
Baniso -1Baniso -2Baniso -3
1-4.96 Å26.81 Å20 Å2
2--4.96 Å20 Å2
3----9.91 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.32 Å0.26 Å
Luzzati d res low-6 Å
Luzzati sigma a0.3 Å0.24 Å
Refinement stepCycle: LAST / Resolution: 2.4→19.73 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2301 0 26 279 2606
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_d22.3
X-RAY DIFFRACTIONc_improper_angle_d0.88
X-RAY DIFFRACTIONc_mcbond_it3.851.5
X-RAY DIFFRACTIONc_mcangle_it5.62
X-RAY DIFFRACTIONc_scbond_it6.352
X-RAY DIFFRACTIONc_scangle_it8.552.5
LS refinement shellResolution: 2.4→2.49 Å / Rfactor Rfree error: 0.023 / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.261 127 10.2 %
Rwork0.226 1123 -
obs-2176 66.9 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PARAMPROTEIN.TOP
X-RAY DIFFRACTION2968.PAR968.TOP
Refine LS restraints
*PLUS
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_dihedral_angle_d
X-RAY DIFFRACTIONc_dihedral_angle_deg22.3
X-RAY DIFFRACTIONc_improper_angle_d
X-RAY DIFFRACTIONc_improper_angle_deg0.88

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