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- PDB-1q1m: A Highly Efficient Approach to a Selective and Cell Active PTP1B ... -

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Entry
Database: PDB / ID: 1q1m
TitleA Highly Efficient Approach to a Selective and Cell Active PTP1B inhibitors
ComponentsProtein-tyrosine phosphatase, non-receptor type 1
KeywordsHYDROLASE / Protein Tyrosine Phosphatase 1B / PTP1B / inhibitors with isoxazole-salicylate pharmacophores
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-234 / Tyrosine-protein phosphatase non-receptor type 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.6 Å
AuthorsLiu, G. / Xin, Z. / Pei, Z. / Hajduk, P.J. / Abad-Zapatero, C. / Hutchins, C.W. / Zhao, H. / Lubben, T.H. / Ballaron, S.J. / Haasch, D.L. ...Liu, G. / Xin, Z. / Pei, Z. / Hajduk, P.J. / Abad-Zapatero, C. / Hutchins, C.W. / Zhao, H. / Lubben, T.H. / Ballaron, S.J. / Haasch, D.L. / Kaszubska, W. / Rondinone, C.M. / Trevillyan, J.M. / Jirousek, M.R.
Citation
Journal: J.Med.Chem. / Year: 2003
Title: Fragment screening and assembly: a highly efficient approach to a selective and cell active protein tyrosine phosphatase 1B inhibitor.
Authors: Liu, G. / Xin, Z. / Pei, Z. / Hajduk, P.J. / Abad-Zapatero, C. / Hutchins, C.W. / Zhao, H. / Lubben, T.H. / Ballaron, S.J. / Haasch, D.L. / Kaszubska, W. / Rondinone, C.M. / Trevillyan, J.M. / Jirousek, M.R.
#1: Journal: 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.H. / Trevillyan, J.M. / Stashko, M.A. / Ballaron, S.J. / Liang, H. / Huang, F. / Hutchins, ...Authors: Szczepankiewicz, B.G. / Liu, G. / Hajduk, P.J. / Abad-Zapatero, C. / Pei, Z. / Xin, Z. / Lubben, T.H. / Trevillyan, J.M. / Stashko, M.A. / Ballaron, S.J. / Liang, H. / Huang, F. / Hutchins, C.W. / Fesik, S.W. / Jirousek, M.R.
#2: Journal: BIOORG.MED.CHEM.LETT. / Year: 2003
Title: Potent, Selective Inhibitors of Protein Tyrosine Phosphatase 1B
Authors: Xin, Z. / Oost, T.K. / Abad-Zapatero, C. / Hajduk, P.J. / Pei, Z. / Szczepankiewicz, B.G. / Hutchins, C.W. / Ballaron, S.J. / Stashko, M.A. / Lubben, T. / Trevillyan, J.M. / Jirousek, M.R. / Liu, G.
#3: Journal: J.Med.Chem. / Year: 2003
Title: Discovery and Structure-Activity Relationship of Oxalylarylaminobenzoic Acids as Inhibitors of Protein Tyrosine Phosphatase 1B
Authors: Liu, G. / Szczepankiewicz, B.G. / Pei, Z. / Janowich, D.A. / Xin, Z. / Hadjuk, P.J. / Abad-Zapatero, C. / Liang, H. / Hutchins, C.W. / Fesik, S.W. / Ballaron, S.J. / Stashko, M.A. / Lubben, ...Authors: Liu, G. / Szczepankiewicz, B.G. / Pei, Z. / Janowich, D.A. / Xin, Z. / Hadjuk, P.J. / Abad-Zapatero, C. / Liang, H. / Hutchins, C.W. / Fesik, S.W. / Ballaron, S.J. / Stashko, M.A. / Lubben, T. / Mika, A.K. / Zinker, B.A. / Trevillyan, J.M. / Jirousek, M.R.
#4: Journal: To be Published
Title: Selective Protein Tyrosine Phosphatase 1B Inhibitors: Targeting the Second Phosphotyrosine Binding Site with Non-Carboxylic Acid-Containing Ligands
Authors: Liu, G. / Xin, Z. / Liang, H. / Abad-Zapatero, C. / Hajduk, P.J. / Janowick, D.A. / Szczepankiewicz, B.G. / Pei, Z. / Hutchins, C.W. / Ballaron, S.J. / Stashko, M.A. / Lubben, T.H. / Berg, C. ...Authors: Liu, G. / Xin, Z. / Liang, H. / Abad-Zapatero, C. / Hajduk, P.J. / Janowick, D.A. / Szczepankiewicz, B.G. / Pei, Z. / Hutchins, C.W. / Ballaron, S.J. / Stashko, M.A. / Lubben, T.H. / Berg, C.E. / Rondinone, C.M. / Trevillyan, J.M. / Jirousek, M.R.
#5: Journal: To be Published
Title: Discovery and SAR of Novel, Potent and Selective Protein Tyrosine Phosphatase 1B Inhibitors
Authors: Pei, Z. / Li, X. / Liu, G. / Abad-Zapatero, C. / Lubben, T. / Zhang, T. / Ballaron, S.J. / Hutchins, C.W. / Trevillyan, J.M. / Jirousek, M.R.
History
DepositionJul 22, 2003Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 16, 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
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / 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: Protein-tyrosine phosphatase, non-receptor type 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,7792
Polymers37,3661
Non-polymers4131
Water2,234124
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)88.294, 88.294, 104.378
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 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(D3) / References: UniProt: P18031, protein-tyrosine-phosphatase
#2: Chemical ChemComp-234 / 5-{2-FLUORO-5-[3-(3-HYDROXY-2-METHOXYCARBONYL-PHENOXY)-PROPENYL]-PHENYL}-ISOXAZOLE-3-CARBOXYLIC ACID / COMPOUND 9


Mass: 413.353 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H16FNO7
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 124 / 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: 3.14 Å3/Da / Density % sol: 60.84 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7.1
Details: Precipitation buffer: 100 mM HEPES, 0.2 M Magnesium Acetate, 14% PEG8000, pH 7.10, VAPOR DIFFUSION, HANGING DROP, temperature 277K
Crystal grow
*PLUS
Method: unknown

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RU300 / Wavelength: 1.5418 Å
DetectorType: MARRESEARCH / Detector: CCD / Date: Jan 23, 2002 / Details: mirrors
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.6→20 Å / Num. all: 14916 / Num. obs: 14064 / % possible obs: 94 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 1 / Redundancy: 7.6 % / Biso Wilson estimate: 28.3 Å2 / Rmerge(I) obs: 0.082 / Rsym value: 0.082 / Net I/σ(I): 11.9
Reflection shellResolution: 2.6→2.69 Å / Redundancy: 2.1 % / Rmerge(I) obs: 0.498 / Mean I/σ(I) obs: 1.7 / Num. unique all: 1464 / Rsym value: 0.498 / % possible all: 75.1

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Processing

Software
NameVersionClassification
CNX2000refinement
MAR345data collection
HKL-2000data scaling
CNX2000phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1TYR and other refined complexes. 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.

1tyr


Resolution: 2.6→18.8 Å / Rfactor Rfree error: 0.006 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 2 / σ(I): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.223 1186 10.2 %RANDOM
Rwork0.187 ---
obs0.208 11613 78.1 %-
all-14922 --
Solvent computationSolvent model: FLAT MODEL / Bsol: 36.2436 Å2 / ksol: 0.409228 e/Å3
Displacement parametersBiso mean: 24.2 Å2
Baniso -1Baniso -2Baniso -3
1--0.69 Å25.81 Å20 Å2
2---0.69 Å20 Å2
3---1.39 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.32 Å0.27 Å
Luzzati d res low-6 Å
Luzzati sigma a0.32 Å0.26 Å
Refinement stepCycle: LAST / Resolution: 2.6→18.8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2435 0 30 124 2589
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.007
X-RAY DIFFRACTIONc_angle_deg1.3
X-RAY DIFFRACTIONc_dihedral_angle_d21.8
X-RAY DIFFRACTIONc_improper_angle_d0.76
X-RAY DIFFRACTIONc_mcbond_it1.551.5
X-RAY DIFFRACTIONc_mcangle_it2.352
X-RAY DIFFRACTIONc_scbond_it2.222
X-RAY DIFFRACTIONc_scangle_it3.292.5
LS refinement shellResolution: 2.6→2.69 Å / Rfactor Rfree error: 0.039 / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.293 57 10.1 %
Rwork0.245 509 -
obs-509 38.6 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PARAMPROTEIN.TOP
X-RAY DIFFRACTION2WATER_REP.PARAM134.TOP
X-RAY DIFFRACTION3ION.PARAM
X-RAY DIFFRACTION4134.PAR
Refine LS restraints
*PLUS
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_dihedral_angle_d
X-RAY DIFFRACTIONc_dihedral_angle_deg21.8
X-RAY DIFFRACTIONc_improper_angle_d
X-RAY DIFFRACTIONc_improper_angle_deg0.76

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