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- PDB-2cne: Structural Insights into the Design of Nonpeptidic Isothiazolidin... -

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Entry
Database: PDB / ID: 2cne
TitleStructural Insights into the Design of Nonpeptidic Isothiazolidinone- Containing Inhibitors of Protein Tyrosine Phosphatase 1B
ComponentsTYROSINE-PROTEIN PHOSPHATASE NON-RECEPTOR TYPE 1
KeywordsHYDROLASE / POLYMORPHISM / PHOSPHORYLATION / PROTEIN PHOSPHATASE / ENDOPLASMIC RETICULUM / OXIDATION / ACETYLATION / PHOSPHATASE
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 / IRE1-mediated unfolded protein response / positive regulation of protein tyrosine kinase activity / platelet-derived growth factor receptor-beta signaling pathway / sorting endosome ...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 / IRE1-mediated unfolded protein response / positive regulation of protein tyrosine kinase activity / platelet-derived growth factor receptor-beta signaling pathway / sorting endosome / negative regulation of vascular associated smooth muscle cell migration / mitochondrial crista / cytoplasmic side of endoplasmic reticulum membrane / 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 JUN kinase activity / positive regulation of systemic arterial blood pressure / negative regulation of MAP kinase activity / vascular endothelial cell response to oscillatory fluid shear stress / regulation of endocytosis / peptidyl-tyrosine dephosphorylation / non-membrane spanning protein tyrosine phosphatase activity / Regulation of IFNA/IFNB signaling / regulation of proteolysis / cellular response to angiotensin / regulation of postsynapse assembly / positive regulation of endothelial cell apoptotic process / growth hormone receptor signaling pathway via JAK-STAT / negative regulation of cell-substrate adhesion / cellular response to unfolded protein / regulation of signal transduction / Regulation of IFNG signaling / negative regulation of signal transduction / Growth hormone receptor signaling / positive regulation of cardiac muscle cell apoptotic process / positive regulation of heart rate / negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway / protein dephosphorylation / endoplasmic reticulum unfolded protein response / MECP2 regulates neuronal receptors and channels / ephrin receptor binding / Insulin receptor recycling / cellular response to platelet-derived growth factor stimulus / cellular response to fibroblast growth factor stimulus / Integrin signaling / protein-tyrosine-phosphatase / negative regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / cellular response to nitric oxide / negative regulation of insulin receptor signaling pathway / protein tyrosine phosphatase activity / protein phosphatase 2A binding / Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells / endosome lumen / insulin receptor binding / response to nutrient levels / Negative regulation of MET activity / cellular response to nerve growth factor stimulus / receptor tyrosine kinase binding / negative regulation of ERK1 and ERK2 cascade / insulin receptor signaling pathway / negative regulation of neuron projection development / actin cytoskeleton organization / cellular response to hypoxia / early endosome / postsynapse / cadherin binding / mitochondrial matrix / negative regulation of cell population proliferation / protein kinase binding / glutamatergic synapse / enzyme binding / endoplasmic reticulum / protein-containing complex / RNA binding / zinc ion binding / cytoplasm / cytosol
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 profile. / Tyrosine-specific protein phosphatases domain / Protein-tyrosine phosphatase-like / Alpha-Beta Complex / Alpha Beta
Similarity search - Domain/homology
Chem-DFJ / Tyrosine-protein phosphatase non-receptor type 1
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsAla, P.J. / Gonneville, L. / Hillman, M. / Becker-Pasha, M. / Yue, E.W. / Douty, B. / Wayland, B. / Polam, P. / Crawley, M.L. / McLaughlin, E. ...Ala, P.J. / Gonneville, L. / Hillman, M. / Becker-Pasha, M. / Yue, E.W. / Douty, B. / Wayland, B. / Polam, P. / Crawley, M.L. / McLaughlin, E. / Sparks, R.B. / Glass, B. / Takvorian, A. / Combs, A.P. / Burn, T.C. / Hollis, G.F. / Wynn, R.
CitationJournal: J.Biol.Chem. / Year: 2006
Title: Structural Insights Into the Design of Nonpeptidic Isothiazolidinone-Containing Inhibitors of Protein- Tyrosine Phosphatase 1B.
Authors: Ala, P.J. / Gonneville, L. / Hillman, M. / Becker-Pasha, M. / Yue, E.W. / Douty, B. / Wayland, B. / Polam, P. / Crawley, M.L. / Mclaughlin, E. / Sparks, R.B. / Glass, B. / Takvorian, A. / ...Authors: Ala, P.J. / Gonneville, L. / Hillman, M. / Becker-Pasha, M. / Yue, E.W. / Douty, B. / Wayland, B. / Polam, P. / Crawley, M.L. / Mclaughlin, E. / Sparks, R.B. / Glass, B. / Takvorian, A. / Combs, A.P. / Burn, T.C. / Hollis, G.F. / Wynn, R.
History
DepositionMay 21, 2006Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 27, 2006Provider: repository / Type: Initial release
Revision 1.1May 8, 2011Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Jul 5, 2017Group: Data collection / Category: diffrn_source / Item: _diffrn_source.type
Revision 1.4Jul 29, 2020Group: Data collection / Derived calculations / Structure summary
Category: chem_comp / entity ...chem_comp / entity / pdbx_chem_comp_identifier / pdbx_entity_nonpoly / struct_site / struct_site_gen
Item: _chem_comp.mon_nstd_flag / _chem_comp.name ..._chem_comp.mon_nstd_flag / _chem_comp.name / _chem_comp.type / _entity.pdbx_description / _pdbx_entity_nonpoly.name
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 1.5Dec 13, 2023Group: Data collection / Database references ...Data collection / Database references / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: TYROSINE-PROTEIN PHOSPHATASE NON-RECEPTOR TYPE 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,7235
Polymers35,5491
Non-polymers1,1744
Water4,324240
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
Unit cell
Length a, b, c (Å)62.110, 70.980, 83.780
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein TYROSINE-PROTEIN PHOSPHATASE NON-RECEPTOR TYPE 1 / PROTEIN-TYROSINE PHOSPHATASE 1B / PTP-1B


Mass: 35549.445 Da / Num. of mol.: 1 / Fragment: CATALYTIC DOMAIN, RESIDUES 1-298
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: P18031, protein-tyrosine-phosphatase
#2: Chemical ChemComp-DFJ / N-({4-[DIFLUORO(PHOSPHONO)METHYL]PHENYL}ACETYL)-L-PHENYLALANYL-4-[DIFLUORO(PHOSPHONO)METHYL]-L-PHENYLALANINAMIDE


Mass: 689.486 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H29F4N3O9P2
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#4: Sugar ChemComp-BOG / octyl beta-D-glucopyranoside / Beta-Octylglucoside / octyl beta-D-glucoside / octyl D-glucoside / octyl glucoside


Type: D-saccharide / Mass: 292.369 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Formula: C14H28O6 / Comment: detergent*YM
IdentifierTypeProgram
b-octylglucosideIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 240 / Source method: isolated from a natural source / Formula: H2O
Compound detailsMAY PLAY AN IMPORTANT ROLE IN CKII- AND P60C-SRC-INDUCED SIGNAL TRANSDUCTION CASCADES (BY SIMILARITY).
Sequence detailsSIX HISTIDINES WERE ADDED BETWEEN THE FIRST AND SECOND RESIDUES, AS A PURIFICATION TAG

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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: 2.6 Å3/Da / Density % sol: 52.65 %
Crystal growpH: 8.5 / Details: 100 MM TRIS, PH 8.5, 1.4-1.8 M AMMONIUM SULFATE

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Data collection

DiffractionMean temperature: 93 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 / Wavelength: 1.5418
DetectorType: RIGAKU MSC RAXIS IV / Detector: IMAGE PLATE / Details: BLUE CONFOCAL MAX-FLUX MIRRORS
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.8→30.5 Å / Num. obs: 33472 / % possible obs: 95.3 % / Observed criterion σ(I): 0 / Redundancy: 2.7 % / Rmerge(I) obs: 0.07 / Net I/σ(I): 10.9
Reflection shellResolution: 1.8→1.86 Å / Redundancy: 2.5 % / Rmerge(I) obs: 0.51 / Mean I/σ(I) obs: 1.7 / % possible all: 92.6

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Processing

Software
NameVersionClassification
CNX2002refinement
CrystalCleardata reduction
CrystalCleardata scaling
CNXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1EEO

1eeo


Resolution: 1.8→10 Å / Cross valid method: THROUGHOUT / σ(F): 1
RfactorNum. reflection% reflectionSelection details
Rfree0.237 3110 8.9 %RANDOM
Rwork0.1974 ---
obs-31127 --
Solvent computationBsol: 280 Å2 / ksol: 0.8 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1--0.129 Å20 Å20 Å2
2---0.05 Å20 Å2
3---0.179 Å2
Refinement stepCycle: LAST / Resolution: 1.8→10 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2349 0 76 240 2665
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.010318
X-RAY DIFFRACTIONc_bond_d_na
X-RAY DIFFRACTIONc_bond_d_prot
X-RAY DIFFRACTIONc_angle_d
X-RAY DIFFRACTIONc_angle_d_na
X-RAY DIFFRACTIONc_angle_d_prot
X-RAY DIFFRACTIONc_angle_deg1.69746
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it
X-RAY DIFFRACTIONc_mcangle_it
X-RAY DIFFRACTIONc_scbond_it
X-RAY DIFFRACTIONc_scangle_it

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