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- PDB-6r5g: C-SH2 domain of SHP-2 in complex with phospho-ITSM of PD-1 -

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Basic information

Entry
Database: PDB / ID: 6r5g
TitleC-SH2 domain of SHP-2 in complex with phospho-ITSM of PD-1
Components
  • ITSM
  • Tyrosine-protein phosphatase non-receptor type 11
KeywordsPEPTIDE BINDING PROTEIN / SHP-2 C-SH2 ITSM SH2 domain PD-1 phosphotyrosine
Function / homology
Function and homology information


negative regulation of immune response / atrioventricular canal development / genitalia development / negative regulation of T cell mediated immune response to tumor cell / STAT5 Activation / Co-inhibition by BTLA / Netrin mediated repulsion signals / negative regulation of neutrophil activation / negative regulation of chondrocyte differentiation / positive regulation of lipopolysaccharide-mediated signaling pathway ...negative regulation of immune response / atrioventricular canal development / genitalia development / negative regulation of T cell mediated immune response to tumor cell / STAT5 Activation / Co-inhibition by BTLA / Netrin mediated repulsion signals / negative regulation of neutrophil activation / negative regulation of chondrocyte differentiation / positive regulation of lipopolysaccharide-mediated signaling pathway / face morphogenesis / Interleukin-37 signaling / positive regulation of ossification / Signaling by Leptin / negative regulation of cell adhesion mediated by integrin / MET activates PTPN11 / Regulation of RUNX1 Expression and Activity / Signal regulatory protein family interactions / ERBB signaling pathway / Interleukin-20 family signaling / Interleukin-6 signaling / PD-L1(CD274) glycosylation and translocation to plasma membrane / Co-inhibition by CTLA4 / PI-3K cascade:FGFR3 / STAT5 activation downstream of FLT3 ITD mutants / Platelet sensitization by LDL / negative regulation of T cell activation / inner ear development / fibroblast growth factor receptor signaling pathway / PI-3K cascade:FGFR2 / PI-3K cascade:FGFR4 / peptide hormone receptor binding / humoral immune response / negative regulation of type I interferon production / MAPK3 (ERK1) activation / PI-3K cascade:FGFR1 / regulation of type I interferon-mediated signaling pathway / MAPK1 (ERK2) activation / Prolactin receptor signaling / PECAM1 interactions / non-membrane spanning protein tyrosine phosphatase activity / peptidyl-tyrosine dephosphorylation / Regulation of IFNA/IFNB signaling / positive regulation of intracellular signal transduction / RET signaling / Interleukin-3, Interleukin-5 and GM-CSF signaling / Co-inhibition by PD-1 / PI3K Cascade / ephrin receptor signaling pathway / positive regulation of insulin receptor signaling pathway / regulation of protein-containing complex assembly / regulation of immune response / negative regulation of T cell receptor signaling pathway / negative regulation of T cell proliferation / Regulation of IFNG signaling / GAB1 signalosome / T cell costimulation / Activated NTRK2 signals through FRS2 and FRS3 / GPVI-mediated activation cascade / Signaling by CSF3 (G-CSF) / FRS-mediated FGFR3 signaling / Signaling by FLT3 ITD and TKD mutants / phosphotyrosine residue binding / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / phosphoprotein phosphatase activity / protein-tyrosine-phosphatase / FRS-mediated FGFR1 signaling / Tie2 Signaling / FLT3 Signaling / protein tyrosine phosphatase activity / cell adhesion molecule binding / positive regulation of interferon-beta production / Downstream signal transduction / cellular response to epidermal growth factor stimulus / protein tyrosine kinase binding / positive regulation of D-glucose import across plasma membrane / insulin receptor binding / Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE) / brain development / Negative regulation of FGFR3 signaling / cellular response to mechanical stimulus / Negative regulation of FGFR2 signaling / Negative regulation of FGFR4 signaling / Negative regulation of FGFR1 signaling / Signaling by SCF-KIT / negative regulation of inflammatory response / Spry regulation of FGF signaling / receptor tyrosine kinase binding / vasodilation / epidermal growth factor receptor signaling pathway / cytokine-mediated signaling pathway / Constitutive Signaling by Aberrant PI3K in Cancer / heart development / Signaling by CSF1 (M-CSF) in myeloid cells / Interferon alpha/beta signaling / positive regulation of tumor necrosis factor production / PIP3 activates AKT signaling / transmembrane signaling receptor activity / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling
Similarity search - Function
Programmed cell death protein 1 / Protein-tyrosine phosphatase, non-receptor type-6, -11 / SH2 domain / SHC Adaptor Protein / 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 ...Programmed cell death protein 1 / Protein-tyrosine phosphatase, non-receptor type-6, -11 / SH2 domain / SHC Adaptor Protein / 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 / SH2 domain / Immunoglobulin V-Type / Immunoglobulin V-set domain / Src homology 2 (SH2) domain profile. / Src homology 2 domains / SH2 domain / SH2 domain superfamily / Immunoglobulin V-set domain / Immunoglobulin subtype / Immunoglobulin / Ig-like domain profile. / Immunoglobulin-like domain / Immunoglobulin-like domain superfamily / Immunoglobulin-like fold / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
Tyrosine-protein phosphatase non-receptor type 11 / Programmed cell death protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodSOLUTION NMR / simulated annealing-molecular dynamics
AuthorsMarasco, M.
Funding support Germany, 1items
OrganizationGrant numberCountry
German Research FoundationCA294/20-1 Germany
CitationJournal: Sci Adv / Year: 2020
Title: Molecular mechanism of SHP2 activation by PD-1 stimulation.
Authors: Marasco, M. / Berteotti, A. / Weyershaeuser, J. / Thorausch, N. / Sikorska, J. / Krausze, J. / Brandt, H.J. / Kirkpatrick, J. / Rios, P. / Schamel, W.W. / Kohn, M. / Carlomagno, T.
History
DepositionMar 25, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 5, 2020Provider: repository / Type: Initial release
Revision 1.1Feb 19, 2020Group: Database references / Category: citation
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.title / _citation.year
Revision 1.2Feb 26, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.3Jun 14, 2023Group: Database references / Other / Category: database_2 / pdbx_database_status
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_nmr_data
Revision 1.4Oct 9, 2024Group: Data collection / Database references / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature
Item: _database_2.pdbx_DOI

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Tyrosine-protein phosphatase non-receptor type 11
B: ITSM


Theoretical massNumber of molelcules
Total (without water)14,6792
Polymers14,6792
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: isothermal titration calorimetry, 1:1 binding with Kd=13nM
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area1420 Å2
ΔGint-11 kcal/mol
Surface area7200 Å2
MethodPISA
NMR ensembles
DataCriteria
Number of conformers (submitted / calculated)10 / 150structures with the lowest energy
RepresentativeModel #1lowest energy

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Components

#1: Protein Tyrosine-protein phosphatase non-receptor type 11 / Protein-tyrosine phosphatase 1D / PTP-1D / Protein-tyrosine phosphatase 2C / PTP-2C / SH-PTP2 / Shp2 / SH-PTP3


Mass: 13301.950 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PTPN11, PTP2C, SHPTP2 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q06124, protein-tyrosine-phosphatase
#2: Protein/peptide ITSM


Mass: 1377.387 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: Q15116*PLUS
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: SOLUTION NMR
NMR experiment
Conditions-IDExperiment-IDSolution-IDSample stateSpectrometer-IDType
113isotropic22D 1H-15N HSQC
123isotropic23D HNCO
133isotropic23D HN(CA)CB
143isotropic23D HN(COCA)CB
153isotropic23D (H)CCH-TOCSY
163isotropic22D 1H-13C HSQC
173isotropic13D NOESY-13C HSQC
183isotropic23D 13C/15N-filtered NOESY-13C HSQC
194isotropic22D 13C/15N-filtered 1H-1H NOESY
1104isotropic22D 13C/15N-filtered 1H-1H TOCSY
1113isotropic13D NOESY-15N HSQC

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Sample preparation

Details
TypeSolution-IDContentsLabelSolvent system
solution3800 uM [U-13C; U-15N] C-SH2 domain of SHP-2, 1000 uM ITSM, 90% H2O/10% D2Opeptide_excess90% H2O/10% D2O
solution4800 uM [U-13C; U-15N] C-SH2 domain of SHP-2, 640 uM ITSM, 90% H2O/10% D2Oprotein_excess90% H2O/10% D2O
Sample
Conc. (mg/ml)ComponentIsotopic labelingSolution-ID
800 uMC-SH2 domain of SHP-2[U-13C; U-15N]3
1000 uMITSMnatural abundance3
800 uMC-SH2 domain of SHP-2[U-13C; U-15N]4
640 uMITSMnatural abundance4
Sample conditionsIonic strength: 150 mM / Label: NMR_sample / pH: 6.8 / Pressure: 1 atm / Temperature: 298 K

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NMR measurement

NMR spectrometer
TypeManufacturerModelField strength (MHz)Spectrometer-ID
Bruker AVANCE III HDBrukerAVANCE III HD8501
Bruker AVANCE III HDBrukerAVANCE III HD6002

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Processing

NMR software
NameDeveloperClassification
TopSpinBruker Biospincollection
CcpNmr AnalysisCCPNpeak picking
CcpNmr AnalysisCCPNchemical shift assignment
ARIALinge, O'Donoghue and Nilgesstructure calculation
CNSBrunger, Adams, Clore, Gros, Nilges and Readstructure calculation
NMRPipeDelaglio, Grzesiek, Vuister, Zhu, Pfeifer and Baxprocessing
Refinement
MethodSoftware ordinalDetails (eV)
simulated annealing-molecular dynamics5ARIA and CNS were used in combination
simulated annealing-molecular dynamics6ARIA and CNS were used in combination
NMR representativeSelection criteria: lowest energy
NMR ensembleConformer selection criteria: structures with the lowest energy
Conformers calculated total number: 150 / Conformers submitted total number: 10

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