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- PDB-2bgd: Structure-based design of Protein Tyrosine Phosphatase-1B Inhibitors -

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Basic information

Entry
Database: PDB / ID: 2bgd
TitleStructure-based design of Protein Tyrosine Phosphatase-1B Inhibitors
ComponentsPROTEIN-TYROSINE PHOSPHATASE NON-RECEPTOR TYPE 1
KeywordsHYDROLASE / PROTEIN TYROSINE PHOSPHATASE / 1 / 2 / 5-THIADIAZOLIDIN-3-ONE-1 / 1-DIOXIDE TEMPLATE
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
PHOSPHATE ION / Chem-T1D / Tyrosine-protein phosphatase non-receptor type 1
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.4 Å
AuthorsBlack, E. / Breed, J. / Breeze, A.L. / Embrey, K. / Garcia, R. / Gero, T.W. / Godfrey, L. / Kenny, P.W. / Morley, A.D. / Minshull, C.A. ...Black, E. / Breed, J. / Breeze, A.L. / Embrey, K. / Garcia, R. / Gero, T.W. / Godfrey, L. / Kenny, P.W. / Morley, A.D. / Minshull, C.A. / Pannifer, A.D. / Read, J. / Rees, A. / Russell, D.J. / Toader, D. / Tucker, J.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2005
Title: Structure-Based Design of Protein Tyrosine Phosphatase-1B Inhibitors
Authors: Black, E. / Breed, J. / Breeze, A.L. / Embrey, K. / Garcia, R. / Gero, T.W. / Godfrey, L. / Kenny, P.W. / Morley, A.D. / Minshull, C.A. / Pannifer, A.D. / Read, J. / Rees, A. / Russell, D.J. ...Authors: Black, E. / Breed, J. / Breeze, A.L. / Embrey, K. / Garcia, R. / Gero, T.W. / Godfrey, L. / Kenny, P.W. / Morley, A.D. / Minshull, C.A. / Pannifer, A.D. / Read, J. / Rees, A. / Russell, D.J. / Toader, D. / Tucker, J.
History
DepositionDec 21, 2004Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 4, 2005Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Advisory / Refinement description / Version format compliance
Revision 1.2Sep 16, 2015Group: Source and taxonomy
Revision 1.3Jul 24, 2019Group: Data collection / Category: diffrn_source / Item: _diffrn_source.pdbx_synchrotron_site
Revision 1.4May 8, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _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)37,9087
Polymers37,3661
Non-polymers5436
Water3,135174
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
Unit cell
Length a, b, c (Å)88.908, 88.908, 104.548
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number152
Space group name H-MP3121

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Components

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Protein , 1 types, 1 molecules A

#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, RESIDUES 1-321
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

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Non-polymers , 5 types, 180 molecules

#2: Chemical ChemComp-T1D / 5-(4-METHOXYBIPHENYL-3-YL)-1,2,5-THIADIAZOLIDIN-3-ONE 1,1-DIOXIDE


Mass: 318.348 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H14N2O4S
#3: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Cl
#4: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: PO4
#5: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 174 / 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: 3.27 Å3/Da / Density % sol: 62.13 %
Crystal growpH: 6.5 / Details: pH 6.50

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: EMBL/DESY, HAMBURG / Beamline: X13 / Wavelength: 1
DetectorDate: Aug 19, 2002
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.4→27.42 Å / Num. obs: 10524 / % possible obs: 98.6 % / Observed criterion σ(I): 1 / Redundancy: 2.89 % / Rmerge(I) obs: 0.06 / Net I/σ(I): 11.2
Reflection shellResolution: 2.4→2.53 Å / Redundancy: 2.79 % / Rmerge(I) obs: 0.17 / Mean I/σ(I) obs: 4.49 / % possible all: 96.3

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Processing

Software
NameVersionClassification
REFMAC5.1.24refinement
MOSFLMdata reduction
SCALAdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.4→29.11 Å / Cor.coef. Fo:Fc: 0.954 / Cor.coef. Fo:Fc free: 0.934 / SU B: 5.317 / SU ML: 0.124 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / ESU R: 0.238 / ESU R Free: 0.188 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.2 963 5.1 %RANDOM
Rwork0.164 ---
obs0.166 17876 98.4 %-
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: 23.17 Å2
Baniso -1Baniso -2Baniso -3
1-0.14 Å20.07 Å20 Å2
2--0.14 Å20 Å2
3----0.21 Å2
Refinement stepCycle: LAST / Resolution: 2.4→29.11 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2398 0 31 174 2603
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0212480
X-RAY DIFFRACTIONr_bond_other_d0.0020.022204
X-RAY DIFFRACTIONr_angle_refined_deg1.4131.963344
X-RAY DIFFRACTIONr_angle_other_deg0.82235151
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.915292
X-RAY DIFFRACTIONr_dihedral_angle_2_deg
X-RAY DIFFRACTIONr_dihedral_angle_3_deg
X-RAY DIFFRACTIONr_dihedral_angle_4_deg
X-RAY DIFFRACTIONr_chiral_restr0.0780.2353
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.022712
X-RAY DIFFRACTIONr_gen_planes_other0.0050.02502
X-RAY DIFFRACTIONr_nbd_refined0.2050.2452
X-RAY DIFFRACTIONr_nbd_other0.240.22505
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other0.0840.21382
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1530.2125
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1040.210
X-RAY DIFFRACTIONr_symmetry_vdw_other0.2460.238
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1350.214
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.5381.51471
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.10422380
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.8831009
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it3.2044.5964
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.4→2.46 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.248 67
Rwork0.18 1207
Refinement TLS params.Method: refined / Origin x: -0.1411 Å / Origin y: 59.7738 Å / Origin z: 15.3343 Å
111213212223313233
T0.0977 Å20.0292 Å20.0001 Å2-0.0088 Å2-0.0015 Å2--0.0247 Å2
L1.2071 °2-0.0631 °2-0.4079 °2-0.9163 °2-0.0939 °2--1.0955 °2
S0.004 Å °0.0243 Å °-0.0172 Å °-0.0076 Å °0.023 Å °-0.0207 Å °0.0605 Å °-0.0717 Å °-0.0271 Å °

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