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- PDB-2h4k: Crystal structure of PTP1B with a monocyclic thiophene inhibitor -

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Basic information

Entry
Database: PDB / ID: 2h4k
TitleCrystal structure of PTP1B with a monocyclic thiophene inhibitor
ComponentsTyrosine-protein phosphatase non-receptor type 1
KeywordsHYDROLASE / protein-drug complex structure
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-509 / Tyrosine-protein phosphatase non-receptor type 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsXu, W. / Wan, Z.-K.
Citation
Journal: Bioorg.Med.Chem.Lett. / Year: 2006
Title: Monocyclic thiophenes as protein tyrosine phosphatase 1B inhibitors: Capturing interactions with Asp48.
Authors: Wan, Z.K. / Lee, J. / Xu, W. / Erbe, D.V. / Joseph-McCarthy, D. / Follows, B.C. / Zhang, Y.L.
#1: Journal: BIOORG.MED.CHEM. / Year: 2006
Title: Bicyclic and Tricyclic Thiophenes as Protein Tyrosine Phosphatase 1B Inhibitors
History
DepositionMay 24, 2006Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 29, 2006Provider: repository / Type: Initial release
Revision 1.1Oct 16, 2007Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Feb 14, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / 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

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Assembly

Deposited unit
A: Tyrosine-protein phosphatase non-receptor type 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,1912
Polymers34,8341
Non-polymers3571
Water2,018112
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)87.996, 87.996, 103.722
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 Tyrosine-protein phosphatase non-receptor type 1 / Protein-tyrosine phosphatase 1B / PTP-1B


Mass: 34833.723 Da / Num. of mol.: 1 / Fragment: catalytic domain of PTP1b
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PTPN1, PTP1B / Production host: Escherichia coli (E. coli) / References: UniProt: P18031, protein-tyrosine-phosphatase
#2: Chemical ChemComp-509 / 4-BROMO-3-(CARBOXYMETHOXY)-5-PHENYLTHIOPHENE-2-CARBOXYLIC ACID


Mass: 357.177 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C13H9BrO5S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 112 / 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: 3.33 Å3/Da / Density % sol: 63.04 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 15% PEG 4000, 0.1M Hepes, 0.2M MgCl2, pH 7.5, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 113 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RU200 / Wavelength: 1.54 Å
DetectorType: RIGAKU RAXIS IV / Detector: IMAGE PLATE / Date: Jan 2, 2002
RadiationMonochromator: YALE MIRRORS / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2.3→20 Å / Num. all: 18915 / Num. obs: 18915 / % possible obs: 100 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2
Reflection shellResolution: 2.3→2.364 Å / % possible all: 100

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Processing

Software
NameVersionClassificationNB
REFMAC5.2.0019refinement
PDB_EXTRACT2data extraction
ADSCdata collection
DENZOdata reduction
SCALEPACKdata scaling
CNSphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.3→19.57 Å / Cor.coef. Fo:Fc: 0.941 / Cor.coef. Fo:Fc free: 0.912 / SU B: 4.436 / SU ML: 0.11 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.265 / ESU R Free: 0.224 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.26 961 4.8 %RANDOM
Rwork0.208 ---
all0.211 19876 --
obs0.211 18915 100 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 65.092 Å2
Baniso -1Baniso -2Baniso -3
1--1.78 Å2-0.89 Å20 Å2
2---1.78 Å20 Å2
3---2.67 Å2
Refinement stepCycle: LAST / Resolution: 2.3→19.57 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2427 0 20 112 2559
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0222502
X-RAY DIFFRACTIONr_angle_refined_deg1.2671.9623374
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.7945296
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.52524.194124
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.0415461
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.1851517
X-RAY DIFFRACTIONr_chiral_restr0.0880.2355
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.021905
X-RAY DIFFRACTIONr_nbd_refined0.1980.21106
X-RAY DIFFRACTIONr_nbtor_refined0.3040.21694
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1370.2150
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2080.229
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.2040.24
X-RAY DIFFRACTIONr_mcbond_it0.6951.51547
X-RAY DIFFRACTIONr_mcangle_it1.1522401
X-RAY DIFFRACTIONr_scbond_it1.74731118
X-RAY DIFFRACTIONr_scangle_it2.7034.5973
LS refinement shellResolution: 2.3→2.364 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.315 61 -
Rwork0.229 1317 -
obs-1378 100 %

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