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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 tolerance induction / regulatory T cell apoptotic process / negative regulation of cortisol secretion / intestinal epithelial cell migration / microvillus organization / negative regulation of growth hormone secretion / genitalia development / atrioventricular canal development / negative regulation of cell adhesion mediated by integrin / STAT5 Activation ...negative regulation of tolerance induction / regulatory T cell apoptotic process / negative regulation of cortisol secretion / intestinal epithelial cell migration / microvillus organization / negative regulation of growth hormone secretion / genitalia development / atrioventricular canal development / negative regulation of cell adhesion mediated by integrin / STAT5 Activation / Netrin mediated repulsion signals / positive regulation of hormone secretion / cerebellar cortex formation / B cell apoptotic process / negative regulation of immune response / positive regulation of T cell apoptotic process / multicellular organismal reproductive process / regulation of protein export from nucleus / positive regulation of ossification / hormone metabolic process / Interleukin-37 signaling / negative regulation of B cell apoptotic process / Signaling by Leptin / negative regulation of chondrocyte differentiation / MET activates PTPN11 / Regulation of RUNX1 Expression and Activity / ERBB signaling pathway / face morphogenesis / Costimulation by the CD28 family / Signal regulatory protein family interactions / peptide hormone receptor binding / negative regulation of type I interferon production / platelet formation / megakaryocyte development / organ growth / CTLA4 inhibitory signaling / triglyceride metabolic process / Platelet sensitization by LDL / Interleukin-20 family signaling / PI-3K cascade:FGFR3 / Interleukin-6 signaling / STAT5 activation downstream of FLT3 ITD mutants / PI-3K cascade:FGFR2 / PI-3K cascade:FGFR4 / Prolactin receptor signaling / PI-3K cascade:FGFR1 / MAPK3 (ERK1) activation / MAPK1 (ERK2) activation / PECAM1 interactions / Bergmann glial cell differentiation / regulation of cell adhesion mediated by integrin / regulation of type I interferon-mediated signaling pathway / phosphoprotein phosphatase activity / inner ear development / neurotrophin TRK receptor signaling pathway / humoral immune response / platelet-derived growth factor receptor signaling pathway / non-membrane spanning protein tyrosine phosphatase activity / RET signaling / peptidyl-tyrosine dephosphorylation / Interleukin-3, Interleukin-5 and GM-CSF signaling / Regulation of IFNA/IFNB signaling / PI3K Cascade / regulation of immune response / PD-1 signaling / regulation of protein-containing complex assembly / ephrin receptor signaling pathway / fibroblast growth factor receptor signaling pathway / GAB1 signalosome / Activated NTRK2 signals through FRS2 and FRS3 / negative regulation of insulin secretion / Regulation of IFNG signaling / positive regulation of insulin receptor signaling pathway / FRS-mediated FGFR3 signaling / Signaling by CSF3 (G-CSF) / Signaling by FLT3 ITD and TKD mutants / homeostasis of number of cells within a tissue / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / Tie2 Signaling / FRS-mediated FGFR1 signaling / cellular response to epidermal growth factor stimulus / cell adhesion molecule binding / GPVI-mediated activation cascade / T cell costimulation / FLT3 Signaling / positive regulation of interferon-beta production / hormone-mediated signaling pathway / phosphotyrosine residue binding / positive regulation of mitotic cell cycle / Downstream signal transduction / protein dephosphorylation / Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE) / protein-tyrosine-phosphatase / axonogenesis / protein tyrosine kinase binding / DNA damage checkpoint signaling / protein tyrosine phosphatase activity / integrin-mediated signaling pathway / positive regulation of glucose import
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 / Tyrosine specific protein phosphatases domain profile. / Protein-tyrosine phosphatase-like / Immunoglobulin V-Type / Immunoglobulin V-set domain / SH2 domain / Src homology 2 (SH2) domain profile. / Src homology 2 domains / SH2 domain / Immunoglobulin V-set domain / SH2 domain superfamily / 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

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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

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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
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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