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- PDB-1no6: Potent, Selective Protein Tyrosine Phosphatase 1B Inhibitor Compo... -

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Basic information

Entry
Database: PDB / ID: 1no6
TitlePotent, Selective Protein Tyrosine Phosphatase 1B Inhibitor Compound 5 Using a Linked-Fragment Strategy
ComponentsProtein-tyrosine phosphatase, non-receptor type 1
KeywordsHYDROLASE / Protein Tyrosine Phosphatase fold / Oxamic Acid Inhibitor bound to P-loop
Function / homology
Function and homology information


PTK6 Down-Regulation / regulation of hepatocyte growth factor receptor signaling pathway / positive regulation of receptor catabolic process / peptidyl-tyrosine dephosphorylation involved in inactivation of protein kinase activity / insulin receptor recycling / negative regulation of vascular endothelial growth factor receptor signaling pathway / positive regulation of IRE1-mediated unfolded protein response / negative regulation of PERK-mediated unfolded protein response / IRE1-mediated unfolded protein response / regulation of intracellular protein transport ...PTK6 Down-Regulation / regulation of hepatocyte growth factor receptor signaling pathway / positive regulation of receptor catabolic process / peptidyl-tyrosine dephosphorylation involved in inactivation of protein kinase activity / insulin receptor recycling / negative regulation of vascular endothelial growth factor receptor signaling pathway / positive regulation of IRE1-mediated unfolded protein response / negative regulation of PERK-mediated unfolded protein response / IRE1-mediated unfolded protein response / regulation of intracellular protein transport / cytoplasmic side of endoplasmic reticulum membrane / sorting endosome / mitochondrial crista / platelet-derived growth factor receptor-beta signaling pathway / regulation of type I interferon-mediated signaling pathway / regulation of endocytosis / positive regulation of protein tyrosine kinase activity / non-membrane spanning protein tyrosine phosphatase activity / peptidyl-tyrosine dephosphorylation / Regulation of IFNA/IFNB signaling / cellular response to unfolded protein / regulation of signal transduction / 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 / Growth hormone receptor signaling / MECP2 regulates neuronal receptors and channels / negative regulation of MAP kinase activity / endoplasmic reticulum unfolded protein response / positive regulation of JUN kinase activity / negative regulation of insulin receptor signaling pathway / Insulin receptor recycling / protein dephosphorylation / ephrin receptor binding / Integrin signaling / protein-tyrosine-phosphatase / protein tyrosine phosphatase activity / protein phosphatase 2A binding / 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 ...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-794 / Tyrosine-protein phosphatase non-receptor type 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.4 Å
AuthorsSzczepankiewicz, 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. ...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.
CitationJournal: J.Am.Chem.Soc. / Year: 2003
Title: Discovery of a 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
DepositionJan 15, 2003Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 8, 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 / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / 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_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

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Assembly

Deposited unit
A: Protein-tyrosine phosphatase, non-receptor type 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,7012
Polymers37,3661
Non-polymers3351
Water4,648258
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)88.900, 88.900, 105.680
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 / Species (production host): Escherichia coli / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(De3) / References: UniProt: P18031, protein-tyrosine-phosphatase
#2: Chemical ChemComp-794 / 2-[(CARBOXYCARBONYL)(1-NAPHTHYL)AMINO]BENZOIC ACID / COMPOUND 5 / 2-(NAPHTHALEN-1-YL-OXALYL-AMINO)-BENZOIC ACID


Mass: 335.310 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H13NO5
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 258 / 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: 61.85 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7.1
Details: Precipitant buffer 100 mM Hepes, 0.2 M Magnesium Acetate, 14% PEG8000, pH 7.1, VAPOR DIFFUSION, HANGING DROP, temperature 277K
Crystal grow
*PLUS
Method: unknown
Components of the solutions
*PLUS
IDConc.Common nameCrystal-IDSol-ID
13-4 mg/mlprotein11
22-4 mMdithiothreitol11

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RU300 / Wavelength: 1.5418 Å
DetectorType: MARRESEARCH / Detector: IMAGE PLATE / Date: Feb 5, 2000 / Details: mirrors
RadiationMonochromator: mirrors / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.35→20 Å / Num. all: 20261 / Num. obs: 18998 / % possible obs: 92.4 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 1 / Redundancy: 5.6 % / Biso Wilson estimate: 42.9 Å2 / Rmerge(I) obs: 0.061 / Rsym value: 0.061 / Net I/σ(I): 29.2
Reflection shellResolution: 2.35→2.43 Å / Redundancy: 3.9 % / Rmerge(I) obs: 0.48 / Mean I/σ(I) obs: 2.6 / Num. unique all: 2015 / Rsym value: 0.48 / % possible all: 94.1

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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: 2.4→19.25 Å / Rfactor Rfree error: 0.009 / 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.
RfactorNum. reflection% reflectionSelection details
Rfree0.267 804 5 %RANDOM
Rwork0.202 ---
all0.206 16677 --
obs0.204 16241 84.1 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 54.8844 Å2 / ksol: 0.37413 e/Å3
Displacement parametersBiso mean: 40.2 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0 Å20 Å2
3---0 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.38 Å0.28 Å
Luzzati d res low-6 Å
Luzzati sigma a0.25 Å0.24 Å
Refinement stepCycle: LAST / Resolution: 2.4→19.25 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2301 0 25 258 2584
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.012
X-RAY DIFFRACTIONc_angle_deg1.5
X-RAY DIFFRACTIONc_dihedral_angle_d23
X-RAY DIFFRACTIONc_improper_angle_d0.84
X-RAY DIFFRACTIONc_mcbond_it1.371.5
X-RAY DIFFRACTIONc_mcangle_it2.282
X-RAY DIFFRACTIONc_scbond_it1.892
X-RAY DIFFRACTIONc_scangle_it2.952.5
LS refinement shellResolution: 2.4→2.49 Å / Rfactor Rfree error: 0.06 / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.402 45 4.6 %
Rwork0.272 935 -
obs-1835 52.2 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PARAMPROTEIN.TOP
X-RAY DIFFRACTION2794.PAR794.TOP
Refine LS restraints
*PLUS
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_dihedral_angle_d
X-RAY DIFFRACTIONc_dihedral_angle_deg23
X-RAY DIFFRACTIONc_improper_angle_d
X-RAY DIFFRACTIONc_improper_angle_deg0.84

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