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- PDB-7ppl: SHP2 catalytic domain in complex with IRS1 (625-639) phosphopepti... -

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Basic information

Entry
Database: PDB / ID: 7ppl
TitleSHP2 catalytic domain in complex with IRS1 (625-639) phosphopeptide (pTyr-632, pSer-636)
Components
  • Insulin receptor substrate 1
  • Tyrosine-protein phosphatase non-receptor type 11,Tyrosine-protein phosphatase non-receptor type 11
KeywordsSIGNALING PROTEIN / IRS1 / Phosphatase / SHP2 / insulin signaling / Insulin receptor substrate 1
Function / homology
Function and homology information


negative regulation of cortisol secretion / intestinal epithelial cell migration / microvillus organization / negative regulation of growth hormone secretion / IRS-related events triggered by IGF1R / genitalia development / atrioventricular canal development / positive regulation of glucose metabolic process / positive regulation of fatty acid beta-oxidation / IRS-mediated signalling ...negative regulation of cortisol secretion / intestinal epithelial cell migration / microvillus organization / negative regulation of growth hormone secretion / IRS-related events triggered by IGF1R / genitalia development / atrioventricular canal development / positive regulation of glucose metabolic process / positive regulation of fatty acid beta-oxidation / IRS-mediated signalling / STAT5 Activation / Co-inhibition by BTLA / Netrin mediated repulsion signals / negative regulation of neutrophil activation / cerebellar cortex formation / insulin receptor complex / transmembrane receptor protein tyrosine kinase adaptor activity / positive regulation of hormone secretion / Activated NTRK3 signals through PI3K / negative regulation of cell adhesion mediated by integrin / regulation of protein export from nucleus / positive regulation of lipopolysaccharide-mediated signaling pathway / Interleukin-37 signaling / Signaling by Leptin / positive regulation of ossification / MET activates PTPN11 / cellular response to fatty acid / hormone metabolic process / negative regulation of chondrocyte differentiation / Regulation of RUNX1 Expression and Activity / Signaling by LTK / Signal regulatory protein family interactions / PI3K/AKT activation / face morphogenesis / platelet formation / ERBB signaling pathway / triglyceride metabolic process / organ growth / Signaling by ALK / megakaryocyte development / Interleukin-20 family signaling / Interleukin-6 signaling / regulation of cell adhesion mediated by integrin / PI-3K cascade:FGFR3 / Co-inhibition by CTLA4 / negative regulation of type I interferon production / STAT5 activation downstream of FLT3 ITD mutants / Platelet sensitization by LDL / IRS activation / peptide hormone receptor binding / PI-3K cascade:FGFR2 / PI-3K cascade:FGFR4 / PI-3K cascade:FGFR1 / MAPK3 (ERK1) activation / neurotrophin TRK receptor signaling pathway / Prolactin receptor signaling / regulation of type I interferon-mediated signaling pathway / MAPK1 (ERK2) activation / platelet-derived growth factor receptor signaling pathway / PECAM1 interactions / Bergmann glial cell differentiation / peptidyl-tyrosine dephosphorylation / inner ear development / non-membrane spanning protein tyrosine phosphatase activity / Regulation of IFNA/IFNB signaling / positive regulation of intracellular signal transduction / RET signaling / Interleukin-3, Interleukin-5 and GM-CSF signaling / PI3K Cascade / Co-inhibition by PD-1 / SOS-mediated signalling / fibroblast growth factor receptor signaling pathway / positive regulation of glycogen biosynthetic process / Signal attenuation / positive regulation of insulin receptor signaling pathway / ephrin receptor signaling pathway / GAB1 signalosome / Growth hormone receptor signaling / regulation of protein-containing complex assembly / Regulation of IFNG signaling / Activated NTRK2 signals through FRS2 and FRS3 / phosphatidylinositol 3-kinase binding / GPVI-mediated activation cascade / Signaling by CSF3 (G-CSF) / FRS-mediated FGFR3 signaling / negative regulation of T cell proliferation / T cell costimulation / Signaling by FLT3 ITD and TKD mutants / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / FRS-mediated FGFR1 signaling / insulin-like growth factor receptor binding / Tie2 Signaling / phosphoprotein phosphatase activity / phosphotyrosine residue binding / hormone-mediated signaling pathway / protein-tyrosine-phosphatase / cell adhesion molecule binding / FLT3 Signaling / signaling adaptor activity
Similarity search - Function
Insulin receptor substrate / Phosphotyrosine-binding domain (IRS1-like) / IRS-type PTB domain profile. / Phosphotyrosine-binding domain / Protein-tyrosine phosphatase, non-receptor type-6, -11 / IRS-type PTB domain / PTB domain (IRS-1 type) / Protein tyrosine phosphatase superfamily / Protein-Tyrosine Phosphatase; Chain A / Protein tyrosine phosphatase, catalytic domain ...Insulin receptor substrate / Phosphotyrosine-binding domain (IRS1-like) / IRS-type PTB domain profile. / Phosphotyrosine-binding domain / Protein-tyrosine phosphatase, non-receptor type-6, -11 / IRS-type PTB domain / PTB domain (IRS-1 type) / Protein tyrosine phosphatase superfamily / Protein-Tyrosine Phosphatase; Chain A / Protein tyrosine phosphatase, catalytic domain / PH 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 / PH domain profile. / Pleckstrin homology domain. / Pleckstrin homology domain / SH2 domain / Src homology 2 (SH2) domain profile. / Src homology 2 domains / SH2 domain / SH2 domain superfamily / PH-like domain superfamily / Alpha-Beta Complex / Alpha Beta
Similarity search - Domain/homology
ETHANOL / Insulin receptor substrate 1 / Tyrosine-protein phosphatase non-receptor type 11
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.53 Å
AuthorsSok, P. / Zeke, A. / Remenyi, A.
Funding support Hungary, 2items
OrganizationGrant numberCountry
National Research Development and Innovation Office (NKFIH)KKP 126963 Hungary
National Research Development and Innovation Office (NKFIH)PD120973 Hungary
Citation
Journal: Nat Commun / Year: 2022
Title: Structural insights into the pSer/pThr dependent regulation of the SHP2 tyrosine phosphatase in insulin and CD28 signaling.
Authors: Zeke, A. / Takacs, T. / Sok, P. / Nemeth, K. / Kirsch, K. / Egri, P. / Poti, A.L. / Bento, I. / Tusnady, G.E. / Remenyi, A.
#1: Journal: Acta Crystallogr D Struct Biol / Year: 2019
Title: Macromolecular structure determination using X-rays, neutrons and electrons: recent developments in Phenix.
Authors: Dorothee Liebschner / Pavel V Afonine / Matthew L Baker / Gábor Bunkóczi / Vincent B Chen / Tristan I Croll / Bradley Hintze / Li Wei Hung / Swati Jain / Airlie J McCoy / Nigel W Moriarty ...Authors: Dorothee Liebschner / Pavel V Afonine / Matthew L Baker / Gábor Bunkóczi / Vincent B Chen / Tristan I Croll / Bradley Hintze / Li Wei Hung / Swati Jain / Airlie J McCoy / Nigel W Moriarty / Robert D Oeffner / Billy K Poon / Michael G Prisant / Randy J Read / Jane S Richardson / David C Richardson / Massimo D Sammito / Oleg V Sobolev / Duncan H Stockwell / Thomas C Terwilliger / Alexandre G Urzhumtsev / Lizbeth L Videau / Christopher J Williams / Paul D Adams /
Abstract: Diffraction (X-ray, neutron and electron) and electron cryo-microscopy are powerful methods to determine three-dimensional macromolecular structures, which are required to understand biological ...Diffraction (X-ray, neutron and electron) and electron cryo-microscopy are powerful methods to determine three-dimensional macromolecular structures, which are required to understand biological processes and to develop new therapeutics against diseases. The overall structure-solution workflow is similar for these techniques, but nuances exist because the properties of the reduced experimental data are different. Software tools for structure determination should therefore be tailored for each method. Phenix is a comprehensive software package for macromolecular structure determination that handles data from any of these techniques. Tasks performed with Phenix include data-quality assessment, map improvement, model building, the validation/rebuilding/refinement cycle and deposition. Each tool caters to the type of experimental data. The design of Phenix emphasizes the automation of procedures, where possible, to minimize repetitive and time-consuming manual tasks, while default parameters are chosen to encourage best practice. A graphical user interface provides access to many command-line features of Phenix and streamlines the transition between programs, project tracking and re-running of previous tasks.
History
DepositionSep 14, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 7, 2022Provider: repository / Type: Initial release
Revision 1.1Sep 28, 2022Group: 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_DOI / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Jan 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.3Oct 23, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Tyrosine-protein phosphatase non-receptor type 11,Tyrosine-protein phosphatase non-receptor type 11
B: Insulin receptor substrate 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,8978
Polymers34,3912
Non-polymers5076
Water2,882160
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: native gel electrophoresis
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2050 Å2
ΔGint-6 kcal/mol
Surface area13400 Å2
MethodPISA
Unit cell
Length a, b, c (Å)54.886, 81.802, 147.629
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

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Components

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


Mass: 32629.900 Da / Num. of mol.: 1 / Mutation: catalytic inactivation: C213S
Source method: isolated from a genetically manipulated source
Details: SHP2 catalytic domain was optimised for crystallisation and missing residues from 315 to 323 (original SHP2 sequence numbering), these missing residues in the optimised construct (74-77) ...Details: SHP2 catalytic domain was optimised for crystallisation and missing residues from 315 to 323 (original SHP2 sequence numbering), these missing residues in the optimised construct (74-77) were replaced to GSSG resideues.,SHP2 catalytic domain was optimised for crystallisation and missing residues from 315 to 323 (original SHP2 sequence numbering), these missing residues in the optimised construct (74-77) were replaced to GSSG resideues.
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 Insulin receptor substrate 1 / IRS-1


Mass: 1760.798 Da / Num. of mol.: 1 / Source method: obtained synthetically / Details: Phosphorylated residues: pTyr-632, pSer-636 / Source: (synth.) Homo sapiens (human) / References: UniProt: P35568
#3: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical ChemComp-EOH / ETHANOL


Mass: 46.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 160 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestN
Has protein modificationY

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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: 2.41 Å3/Da / Density % sol: 48.94 % / Description: rhomboid shaped crystal
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 10% PEG 20000, 100mM HEPES buffer pH 7.5, 50mM EDTA

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Data collection

DiffractionMean temperature: 100 K / Ambient temp details: nitrogen gas cryostream / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: PETRA III, EMBL c/o DESY / Beamline: P14 (MX2) / Wavelength: 0.9762 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Aug 3, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9762 Å / Relative weight: 1
ReflectionResolution: 1.53→73.81 Å / Num. obs: 50545 / % possible obs: 100 % / Redundancy: 13.2 % / CC1/2: 1 / Rmerge(I) obs: 0.055 / Rpim(I) all: 0.016 / Rrim(I) all: 0.057 / Net I/σ(I): 24.3 / Num. measured all: 669091
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
1.53-1.5613.51.0033341324740.8850.2811.0432.5100
8.38-73.8112.10.02644053650.9990.0080.02792.899.9

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
XDSdata reduction
Aimless0.7.4data scaling
PHASERphasing
PHENIX1.17refinement
PDB_EXTRACT3.27data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3ZM0

3zm0


Resolution: 1.53→45.58 Å / SU ML: 0.167 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 20.4612
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1972 1998 3.96 %
Rwork0.1762 48484 -
obs0.177 50482 99.96 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 30.07 Å2
Refinement stepCycle: LAST / Resolution: 1.53→45.58 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2329 0 33 160 2522
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0162474
X-RAY DIFFRACTIONf_angle_d1.37633348
X-RAY DIFFRACTIONf_chiral_restr0.0954350
X-RAY DIFFRACTIONf_plane_restr0.0079437
X-RAY DIFFRACTIONf_dihedral_angle_d21.4068941
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.53-1.570.28221400.2573409X-RAY DIFFRACTION99.94
1.57-1.610.24531430.22923439X-RAY DIFFRACTION99.94
1.61-1.660.24291400.22043422X-RAY DIFFRACTION99.94
1.66-1.710.30071420.20573427X-RAY DIFFRACTION99.97
1.71-1.770.2311400.2023430X-RAY DIFFRACTION99.97
1.77-1.840.23081410.19543409X-RAY DIFFRACTION100
1.84-1.930.21441400.18433412X-RAY DIFFRACTION100
1.93-2.030.21851430.19083474X-RAY DIFFRACTION100
2.03-2.160.23211430.1843464X-RAY DIFFRACTION100
2.16-2.320.20641420.17383450X-RAY DIFFRACTION100
2.32-2.560.20271440.18293493X-RAY DIFFRACTION100
2.56-2.930.18391430.17783480X-RAY DIFFRACTION99.97
2.93-3.690.18081470.16633527X-RAY DIFFRACTION99.97
3.69-45.580.16721500.15473648X-RAY DIFFRACTION99.82

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