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- PDB-9c55: Crystal structure of human PTPN2 in complex with active site inhibitor -

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Basic information

Entry
Database: PDB / ID: 9c55
TitleCrystal structure of human PTPN2 in complex with active site inhibitor
ComponentsTyrosine-protein phosphatase non-receptor type 2
KeywordsHYDROLASE/INHIBITOR / phosphatase / apo / HYDROLASE / HYDROLASE-INHIBITOR complex
Function / homology
Function and homology information


negative regulation of interleukin-2-mediated signaling pathway / negative regulation of interleukin-4-mediated signaling pathway / negative regulation of positive thymic T cell selection / positive regulation of PERK-mediated unfolded protein response / negative regulation of platelet-derived growth factor receptor-beta signaling pathway / negative regulation of macrophage colony-stimulating factor signaling pathway / negative regulation of interleukin-6-mediated signaling pathway / regulation of type II interferon-mediated signaling pathway / negative regulation of macrophage differentiation / positive regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway ...negative regulation of interleukin-2-mediated signaling pathway / negative regulation of interleukin-4-mediated signaling pathway / negative regulation of positive thymic T cell selection / positive regulation of PERK-mediated unfolded protein response / negative regulation of platelet-derived growth factor receptor-beta signaling pathway / negative regulation of macrophage colony-stimulating factor signaling pathway / negative regulation of interleukin-6-mediated signaling pathway / regulation of type II interferon-mediated signaling pathway / negative regulation of macrophage differentiation / positive regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway / negative regulation of chemotaxis / negative regulation of tyrosine phosphorylation of STAT protein / negative regulation of receptor signaling pathway via JAK-STAT / Interleukin-37 signaling / syntaxin binding / negative regulation of type I interferon-mediated signaling pathway / negative regulation of T cell receptor signaling pathway / STAT family protein binding / regulation of hepatocyte growth factor receptor signaling pathway / insulin receptor recycling / negative regulation of epidermal growth factor receptor signaling pathway / negative regulation of type II interferon-mediated signaling pathway / endoplasmic reticulum-Golgi intermediate compartment / non-membrane spanning protein tyrosine phosphatase activity / negative regulation of lipid storage / peptidyl-tyrosine dephosphorylation / T cell differentiation / negative regulation of tumor necrosis factor-mediated signaling pathway / Regulation of IFNG signaling / positive regulation of gluconeogenesis / negative regulation of insulin receptor signaling pathway / protein-tyrosine-phosphatase / B cell differentiation / erythrocyte differentiation / protein tyrosine phosphatase activity / endosome lumen / PKR-mediated signaling / Negative regulation of MET activity / receptor tyrosine kinase binding / negative regulation of ERK1 and ERK2 cascade / negative regulation of inflammatory response / integrin binding / insulin receptor signaling pathway / glucose homeostasis / negative regulation of cell population proliferation / protein kinase binding / negative regulation of transcription by RNA polymerase II / endoplasmic reticulum / nucleoplasm / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Protein-tyrosine phosphatase, non-receptor type-1/2 / : / 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 ...Protein-tyrosine phosphatase, non-receptor type-1/2 / : / 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
Similarity search - Domain/homology
Chem-527 / Tyrosine-protein phosphatase non-receptor type 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.36 Å
AuthorsBester, S.M. / Linwood, R. / Wu, W.-I. / Mou, T.-C.
Funding support United States, 1items
OrganizationGrant numberCountry
Other private United States
CitationJournal: Acta Crystallogr.,Sect.F / Year: 2024
Title: Enhancing the apo protein tyrosine phosphatase non-receptor type 2 crystal soaking strategy through inhibitor-accessible binding sites.
Authors: Bester, S.M. / Linwood, R. / Kataoka, R. / Wu, W.I. / Mou, T.C.
History
DepositionJun 5, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 4, 2024Provider: repository / Type: Initial release
Revision 1.1Sep 18, 2024Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Sep 25, 2024Group: Database references / Category: citation_author / Item: _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Tyrosine-protein phosphatase non-receptor type 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,3252
Polymers36,7161
Non-polymers6101
Water3,117173
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)83.392, 223.052, 36.585
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221
Space group name HallC2c2
Symmetry operation#1: x,y,z
#2: x,-y,-z
#3: -x,y,-z+1/2
#4: -x,-y,z+1/2
#5: x+1/2,y+1/2,z
#6: x+1/2,-y+1/2,-z
#7: -x+1/2,y+1/2,-z+1/2
#8: -x+1/2,-y+1/2,z+1/2
Components on special symmetry positions
IDModelComponents
11A-622-

HOH

21A-669-

HOH

31A-671-

HOH

41A-672-

HOH

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Components

#1: Protein Tyrosine-protein phosphatase non-receptor type 2 / T-cell protein-tyrosine phosphatase / TCPTP


Mass: 36715.621 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PTPN2, PTPT / Production host: Escherichia coli (E. coli) / References: UniProt: P17706, protein-tyrosine-phosphatase
#2: Chemical ChemComp-527 / 5-(3-{[1-(BENZYLSULFONYL)PIPERIDIN-4-YL]AMINO}PHENYL)-4-BROMO-3-(CARBOXYMETHOXY)THIOPHENE-2-CARBOXYLIC ACID


Mass: 609.509 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H25BrN2O7S2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 173 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.32 Å3/Da / Density % sol: 46.91 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 100mM MES/imidazole pH6.5, 7% w/v Peg 8000, 14% v/v ethylene glycol, 30mM sodium l-glutamate, 30mM dl-alanine, 30mM glycine, 30mM dl-lysine HCl, 30mM dl-serine

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Apr 1, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.36→78.11 Å / Num. obs: 14667 / % possible obs: 100 % / Redundancy: 6.5 % / Biso Wilson estimate: 42.25 Å2 / CC1/2: 0.998 / Rpim(I) all: 0.044 / Rrim(I) all: 0.111 / Net I/σ(I): 12.7
Reflection shellResolution: 2.36→2.49 Å / Mean I/σ(I) obs: 2.4 / Num. unique obs: 2106 / CC1/2: 0.873 / Rpim(I) all: 0.321 / Rrim(I) all: 0.815

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
autoPROCdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.36→41.7 Å / SU ML: 0.2596 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 24.5022
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2339 708 4.83 %
Rwork0.1988 13939 -
obs0.2005 14647 99.86 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 53.45 Å2
Refinement stepCycle: LAST / Resolution: 2.36→41.7 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2317 0 37 173 2527
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00292439
X-RAY DIFFRACTIONf_angle_d0.54853314
X-RAY DIFFRACTIONf_chiral_restr0.0443352
X-RAY DIFFRACTIONf_plane_restr0.0038429
X-RAY DIFFRACTIONf_dihedral_angle_d14.9346898
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.36-2.540.30141400.26922740X-RAY DIFFRACTION99.97
2.54-2.80.30011430.24642735X-RAY DIFFRACTION99.9
2.8-3.20.24471450.2172729X-RAY DIFFRACTION99.93
3.2-4.030.22841490.17722793X-RAY DIFFRACTION99.83
4.03-41.70.2021310.18292942X-RAY DIFFRACTION99.74
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
15.01074091638-0.8136652026851.272972057253.86033960444-2.564962107985.72958985520.3881251561420.113432909655-0.664959228287-0.26857350767-0.04807175379060.9465961946621.020918635-0.0941387462989-0.1812818354690.563630505651-0.1568886063440.005593573759520.489638157266-0.1320946058340.82796949310710.367051643513.2209802901-10.288750768
24.05979442126-0.252363625090.7546154512682.62047676820.498357316984.49913895862-0.260366206520.0245254236713-0.02479030402060.1470090594180.03511975222680.539339863717-0.123413011975-0.2850075639820.1827760462130.2541038065830.04201808374270.05461652941810.2731968142910.009703577754950.31473148953917.500965421642.4904161575-5.6292237021
31.846633314840.05576339893880.9317986797973.182145205291.128844454822.61241274978-0.097069224863-0.0198786389749-0.0301397842130.378269828440.143998953044-0.02176541716040.1290891691070.162844530303-0.04608970569530.2784275388450.06540168511210.0221757604920.3498155030630.0137729900660.21874861318232.077280769734.363388904-1.1938257931
44.606109986851.095175477651.474070823914.93837697805-0.8027115160794.969085943240.0402262902942-0.273537694791-0.5567581355810.763759783537-0.04031020340270.6009227952470.660810018739-0.0326800910425-0.04826643293510.493784308897-0.007258608295350.1607405790150.348355465144-0.04101728229170.49876487345818.480965710820.4894765567-2.03629016527
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION / Auth asym-ID: A / Label asym-ID: A

IDRefine TLS-IDSelection detailsAuth seq-IDLabel seq-ID
11chain 'A' and (resid 2 through 27 )2 - 271 - 26
22chain 'A' and (resid 28 through 103 )28 - 10327 - 102
33chain 'A' and (resid 104 through 221 )104 - 221103 - 220
44chain 'A' and (resid 222 through 296 )222 - 296221 - 288

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