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- PDB-7uad: Crystal structure of human PTPN2 with inhibitor ABBV-CLS-484 -

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Basic information

Entry
Database: PDB / ID: 7uad
TitleCrystal structure of human PTPN2 with inhibitor ABBV-CLS-484
ComponentsTyrosine-protein phosphatase non-receptor type 2
KeywordsSIGNALING PROTEIN/INHIBITOR / phosphatase / inhibitor / SIGNALING PROTEIN-INHIBITOR complex
Function / homology
Function and homology information


negative regulation of interleukin-2-mediated signaling pathway / negative regulation of positive thymic T cell selection / positive regulation of PERK-mediated unfolded protein response / negative regulation of interleukin-4-mediated signaling pathway / 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 / negative regulation of tyrosine phosphorylation of STAT protein ...negative regulation of interleukin-2-mediated signaling pathway / negative regulation of positive thymic T cell selection / positive regulation of PERK-mediated unfolded protein response / negative regulation of interleukin-4-mediated signaling pathway / 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 / negative regulation of tyrosine phosphorylation of STAT protein / negative regulation of chemotaxis / positive regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway / negative regulation of receptor signaling pathway via JAK-STAT / Interleukin-37 signaling / syntaxin binding / negative regulation of type I interferon-mediated signaling pathway / regulation of hepatocyte growth factor receptor signaling pathway / negative regulation of T cell receptor signaling pathway / STAT family protein binding / insulin receptor recycling / negative regulation of type II interferon-mediated signaling pathway / endoplasmic reticulum-Golgi intermediate compartment / negative regulation of epidermal growth factor receptor signaling pathway / peptidyl-tyrosine dephosphorylation / negative regulation of lipid storage / T cell differentiation / negative regulation of tumor necrosis factor-mediated signaling pathway / Regulation of IFNG signaling / non-membrane spanning protein tyrosine phosphatase activity / positive regulation of gluconeogenesis / protein-tyrosine-phosphatase / B cell differentiation / protein tyrosine phosphatase activity / negative regulation of insulin receptor signaling pathway / erythrocyte differentiation / endosome lumen / Negative regulation of MET activity / negative regulation of ERK1 and ERK2 cascade / PKR-mediated signaling / receptor tyrosine kinase binding / 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-M5R / Tyrosine-protein phosphatase non-receptor type 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.044 Å
AuthorsLongenecker, K.L. / Qiu, W. / Sun, Q. / Frost, J.M.
CitationJournal: Nature / Year: 2023
Title: The PTPN2/PTPN1 inhibitor ABBV-CLS-484 unleashes potent anti-tumour immunity.
Authors: Baumgartner, C.K. / Ebrahimi-Nik, H. / Iracheta-Vellve, A. / Hamel, K.M. / Olander, K.E. / Davis, T.G.R. / McGuire, K.A. / Halvorsen, G.T. / Avila, O.I. / Patel, C.H. / Kim, S.Y. / Kammula, ...Authors: Baumgartner, C.K. / Ebrahimi-Nik, H. / Iracheta-Vellve, A. / Hamel, K.M. / Olander, K.E. / Davis, T.G.R. / McGuire, K.A. / Halvorsen, G.T. / Avila, O.I. / Patel, C.H. / Kim, S.Y. / Kammula, A.V. / Muscato, A.J. / Halliwill, K. / Geda, P. / Klinge, K.L. / Xiong, Z. / Duggan, R. / Mu, L. / Yeary, M.D. / Patti, J.C. / Balon, T.M. / Mathew, R. / Backus, C. / Kennedy, D.E. / Chen, A. / Longenecker, K. / Klahn, J.T. / Hrusch, C.L. / Krishnan, N. / Hutchins, C.W. / Dunning, J.P. / Bulic, M. / Tiwari, P. / Colvin, K.J. / Chuong, C.L. / Kohnle, I.C. / Rees, M.G. / Boghossian, A. / Ronan, M. / Roth, J.A. / Wu, M.J. / Suermondt, J.S.M.T. / Knudsen, N.H. / Cheruiyot, C.K. / Sen, D.R. / Griffin, G.K. / Golub, T.R. / El-Bardeesy, N. / Decker, J.H. / Yang, Y. / Guffroy, M. / Fossey, S. / Trusk, P. / Sun, I.M. / Liu, Y. / Qiu, W. / Sun, Q. / Paddock, M.N. / Farney, E.P. / Matulenko, M.A. / Beauregard, C. / Frost, J.M. / Yates, K.B. / Kym, P.R. / Manguso, R.T.
History
DepositionMar 12, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 26, 2023Provider: repository / Type: Initial release
Revision 1.1Oct 4, 2023Group: Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / citation_author
Item: _citation.pdbx_database_id_DOI
Revision 1.2Oct 18, 2023Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name
Revision 1.3Nov 8, 2023Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last

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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)38,3512
Polymers37,9661
Non-polymers3851
Water2,612145
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area12630 Å2
MethodPISA
Unit cell
Length a, b, c (Å)73.65, 142.78, 77.95
Angle α, β, γ (deg.)90, 90, 90
Int Tables number20
Space group name H-MC2221
Components on special symmetry positions
IDModelComponents
11A-616-

HOH

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Components

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


Mass: 37966.000 Da / Num. of mol.: 1 / Fragment: UNP residues 1-314
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PTPN2, PTPT / Plasmid: pET28b / Production host: Escherichia coli (E. coli) / References: UniProt: P17706, protein-tyrosine-phosphatase
#2: Chemical ChemComp-M5R / 5-{(7R)-1-fluoro-3-hydroxy-7-[(3-methylbutyl)amino]-5,6,7,8-tetrahydronaphthalen-2-yl}-1lambda~6~,2,5-thiadiazolidine-1,1,3-trione


Mass: 385.454 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H24FN3O4S / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 145 / 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: 2.7 Å3/Da / Density % sol: 54.42 %
Crystal growTemperature: 290 K / Method: vapor diffusion, sitting drop
Details: 25% PEG3350, 0.2 M ammonium sulfate, 0.1 M Tris, pH 8.5

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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 EIGER2 X 9M / Detector: PIXEL / Date: Aug 1, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.044→71.385 Å / Num. obs: 17024 / % possible obs: 88.1 % / Redundancy: 6.4 % / Rpim(I) all: 0.036 / Net I/σ(I): 13.3
Reflection shellResolution: 2.044→2.263 Å / Redundancy: 5.9 % / Mean I/σ(I) obs: 1.6 / Num. unique obs: 851 / Rpim(I) all: 0.535 / % possible all: 50.5

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Processing

Software
NameVersionClassification
BUSTER2.11.8refinement
XDSNov 11, 201data reduction
autoPROC1.1.7data scaling
STARANISO2.3.79betadata scaling
PHASER2.8.3phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 1L8K

1l8k


Resolution: 2.044→71.39 Å / Cor.coef. Fo:Fc: 0.947 / Cor.coef. Fo:Fc free: 0.92 / SU R Cruickshank DPI: 0.279 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.293 / SU Rfree Blow DPI: 0.222 / SU Rfree Cruickshank DPI: 0.219
RfactorNum. reflection% reflectionSelection details
Rfree0.2452 804 -RANDOM
Rwork0.2033 ---
obs0.2053 17024 64.4 %-
Displacement parametersBiso mean: 51.37 Å2
Baniso -1Baniso -2Baniso -3
1--0.3385 Å20 Å20 Å2
2--0.1521 Å20 Å2
3---0.1865 Å2
Refine analyzeLuzzati coordinate error obs: 0.29 Å
Refinement stepCycle: LAST / Resolution: 2.044→71.39 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2273 0 26 145 2444
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0082357HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.953198HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d837SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes410HARMONIC5
X-RAY DIFFRACTIONt_it2357HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion297SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact1936SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion3.27
X-RAY DIFFRACTIONt_other_torsion18.64
LS refinement shellResolution: 2.044→2.19 Å
RfactorNum. reflection% reflection
Rfree0.2753 18 -
Rwork0.2826 --
obs--8.69 %

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