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- PDB-2f6y: Protein tyrosine phosphatase 1B with sulfamic acid inhibitors -

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Basic information

Entry
Database: PDB / ID: 2f6y
TitleProtein tyrosine phosphatase 1B with sulfamic acid inhibitors
ComponentsTyrosine-protein phosphatase, non-receptor type 1
KeywordsHYDROLASE / PTP1B / sulfamic acids / tetrahydroisoquinoline / phosphatase / tyrosine
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 / positive regulation of systemic arterial blood pressure / regulation of type I interferon-mediated signaling pathway / negative regulation of PERK-mediated unfolded protein response / 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 / protein dephosphorylation / MECP2 regulates neuronal receptors and channels / Insulin receptor recycling / cellular response to platelet-derived growth factor stimulus / ephrin receptor binding / protein tyrosine phosphatase activity / Integrin signaling / 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-ENT / Tyrosine-protein phosphatase non-receptor type 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.15 Å
AuthorsEvdokimov, A.G. / Pokross, M.E. / Klopfenstein, S.R.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2006
Title: 1,2,3,4-Tetrahydroisoquinolinyl sulfamic acids as phosphatase PTP1B inhibitors
Authors: Klopfenstein, S.R. / Evdokimov, A.G. / Colson, A.-O. / Fairweather, N.T. / Neuman, J.J. / Maier, M.B. / Gray, J.L. / Gerwe, G.S. / Stake, G.E. / Howard, B.W. / Farmer, J.A. / Pokross, M.E. / ...Authors: Klopfenstein, S.R. / Evdokimov, A.G. / Colson, A.-O. / Fairweather, N.T. / Neuman, J.J. / Maier, M.B. / Gray, J.L. / Gerwe, G.S. / Stake, G.E. / Howard, B.W. / Farmer, J.A. / Pokross, M.E. / Downs, T.R. / Kasibhatla, B. / Peters, K.G.
History
DepositionNov 29, 2005Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 13, 2005Provider: repository / Type: Initial release
Revision 1.1May 1, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Advisory / Version format compliance
Revision 1.3Aug 23, 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 / pdbx_struct_conn_angle / struct_conn / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_symmetry / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_symmetry / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_symmetry / _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)35,3088
Polymers34,7211
Non-polymers5877
Water5,873326
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)88.161, 88.161, 104.350
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: 34720.566 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) / Gene: PTPN1, PTP1B / Plasmid: pET28a / 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-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#3: Chemical
ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: Cl
#4: Chemical ChemComp-ENT / 3(R)-METHYLCARBAMOYL-7-SULFOAMINO-3,4-DIHYDRO-1H-ISOQUINOLINE-2-CARBOXYLIC ACID TERT-BUTYL ESTER


Mass: 385.435 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H23N3O6S
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 326 / 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: 3.37 Å3/Da / Density % sol: 63.49 %
Crystal growTemperature: 298 K / Method: vapor diffusion / pH: 8
Details: 18% PEG4000, 200 mM MgCl2, 100 mM TRIS-HCl, pH 8.0, VAPOR DIFFUSION, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: MACSCIENCE / Wavelength: 1.5418 Å
DetectorType: BRUKER SMART 6000 / Detector: CCD / Date: Apr 4, 2001
RadiationMonochromator: SILICON / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.15→31 Å / Num. all: 24796 / Num. obs: 24796 / % possible obs: 95.2 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 4.2 % / Biso Wilson estimate: 31.1 Å2 / Rmerge(I) obs: 0.06 / Net I/σ(I): 12.34
Reflection shellResolution: 2.15→2.25 Å / Redundancy: 3.8 % / Rmerge(I) obs: 0.33 / Mean I/σ(I) obs: 3.16 / Num. unique all: 3118 / % possible all: 95.7

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Processing

Software
NameVersionClassificationNB
REFMACrefinement
PDB_EXTRACT1.701data extraction
HKL-2000data reduction
SCALEPACKdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1PTV

1ptv


Resolution: 2.15→31 Å / Cor.coef. Fo:Fc: 0.966 / Cor.coef. Fo:Fc free: 0.945 / SU B: 6.952 / SU ML: 0.097 / TLS residual ADP flag: LIKELY RESIDUAL / Isotropic thermal model: isotropic / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 0 / ESU R: 0.169 / ESU R Free: 0.157 / Stereochemistry target values: Engh & Huber / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.203 1268 5.1 %RANDOM
Rwork0.158 ---
all0.16 24796 --
obs0.16 24796 95.35 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 31.657 Å2
Baniso -1Baniso -2Baniso -3
1--0.42 Å2-0.21 Å20 Å2
2---0.42 Å20 Å2
3---0.63 Å2
Refinement stepCycle: LAST / Resolution: 2.15→31 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2427 0 32 326 2785
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0222554
X-RAY DIFFRACTIONr_angle_refined_deg2.2871.9673461
X-RAY DIFFRACTIONr_dihedral_angle_1_deg8.0875312
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.82424.219128
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.2915473
X-RAY DIFFRACTIONr_dihedral_angle_4_deg24.2451518
X-RAY DIFFRACTIONr_chiral_restr0.1530.2367
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.021950
X-RAY DIFFRACTIONr_nbd_refined0.2290.21152
X-RAY DIFFRACTIONr_nbtor_refined0.3140.21747
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.2360.2248
X-RAY DIFFRACTIONr_metal_ion_refined0.3310.22
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.3940.282
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1960.222
X-RAY DIFFRACTIONr_mcbond_it1.561.51561
X-RAY DIFFRACTIONr_mcangle_it2.35522450
X-RAY DIFFRACTIONr_scbond_it3.88431144
X-RAY DIFFRACTIONr_scangle_it5.8674.51003
LS refinement shellResolution: 2.15→2.206 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.24 83 -
Rwork0.182 1708 -
obs-1791 94.31 %
Refinement TLS params.Method: refined / Origin x: 43.9569 Å / Origin y: 16.9073 Å / Origin z: 2.157 Å
111213212223313233
T0.0113 Å2-0.0218 Å20.0026 Å2--0.0572 Å2-0.0062 Å2---0.0487 Å2
L0.6646 °20.2614 °20.303 °2-0.7178 °2-0.1854 °2--0.625 °2
S0.0336 Å °-0.0416 Å °-0.0322 Å °0.0158 Å °-0.0145 Å °-0.0236 Å °-0.0252 Å °-0.0554 Å °-0.0191 Å °
Refinement TLS groupSelection: ALL

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