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- PDB-7ppm: SHP2 catalytic domain in complex with IRS1 (889-901) phosphopepti... -

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Basic information

Entry
Database: PDB / ID: 7ppm
TitleSHP2 catalytic domain in complex with IRS1 (889-901) phosphopeptide (pSer-892, pTyr-896)
Components
  • Insulin receptor substrate 1
  • Tyrosine-protein phosphatase non-receptor type 11,Tyrosine-protein phosphatase non-receptor type 11
KeywordsSIGNALING PROTEIN / SHP2 / IRS1 / Phosphatase / phosphopeptide / 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 / negative regulation of cell adhesion mediated by integrin ...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 / negative regulation of cell adhesion mediated by integrin / STAT5 Activation / Co-inhibition by BTLA / IRS-mediated signalling / Netrin mediated repulsion signals / negative regulation of neutrophil activation / cerebellar cortex formation / insulin receptor complex / positive regulation of hormone secretion / Activated NTRK3 signals through PI3K / transmembrane receptor protein tyrosine kinase adaptor activity / regulation of protein export from nucleus / Interleukin-37 signaling / positive regulation of lipopolysaccharide-mediated signaling pathway / positive regulation of ossification / Signaling by Leptin / MET activates PTPN11 / cellular response to fatty acid / hormone metabolic process / Regulation of RUNX1 Expression and Activity / negative regulation of chondrocyte differentiation / Signaling by LTK / Signal regulatory protein family interactions / face morphogenesis / PI3K/AKT activation / ERBB signaling pathway / platelet formation / triglyceride metabolic process / megakaryocyte development / negative regulation of type I interferon production / organ growth / Signaling by ALK / Interleukin-20 family signaling / Interleukin-6 signaling / PI-3K cascade:FGFR3 / Co-inhibition by CTLA4 / Platelet sensitization by LDL / STAT5 activation downstream of FLT3 ITD mutants / peptide hormone receptor binding / PI-3K cascade:FGFR2 / IRS activation / PI-3K cascade:FGFR4 / PI-3K cascade:FGFR1 / MAPK3 (ERK1) activation / Prolactin receptor signaling / neurotrophin TRK receptor signaling pathway / regulation of cell adhesion mediated by integrin / regulation of type I interferon-mediated signaling pathway / MAPK1 (ERK2) activation / platelet-derived growth factor receptor signaling pathway / PECAM1 interactions / Bergmann glial cell differentiation / inner ear development / peptidyl-tyrosine dephosphorylation / non-membrane spanning protein tyrosine phosphatase activity / positive regulation of intracellular signal transduction / phosphoprotein phosphatase activity / Regulation of IFNA/IFNB signaling / 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 insulin receptor signaling pathway / GAB1 signalosome / positive regulation of glycogen biosynthetic process / ephrin receptor signaling pathway / Signal attenuation / regulation of protein-containing complex assembly / Regulation of IFNG signaling / Activated NTRK2 signals through FRS2 and FRS3 / Growth hormone receptor signaling / phosphatidylinositol 3-kinase binding / GPVI-mediated activation cascade / FRS-mediated FGFR3 signaling / Signaling by CSF3 (G-CSF) / cell adhesion molecule binding / negative regulation of T cell proliferation / Signaling by FLT3 ITD and TKD mutants / T cell costimulation / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / FRS-mediated FGFR1 signaling / hormone-mediated signaling pathway / Tie2 Signaling / insulin-like growth factor receptor binding / signaling adaptor activity / phosphotyrosine residue binding / protein-tyrosine-phosphatase / FLT3 Signaling
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 / PTP type protein phosphatase domain profile. / Protein-tyrosine phosphatase / Tyrosine-specific protein phosphatase, PTPase domain / PH 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
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: 1.48 Å
AuthorsSok, P. / Zeke, A. / Remenyi, A.
Funding support Hungary, 2items
OrganizationGrant numberCountry
Hungarian National Research, Development and Innovation OfficePD120973 Hungary
National Research Development and Innovation Office (NKFIH)KKP 126963 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 1.3Nov 20, 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)34,3923
Polymers34,2992
Non-polymers921
Water2,234124
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: native gel electrophoresis
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1040 Å2
ΔGint-8 kcal/mol
Surface area13240 Å2
MethodPISA
Unit cell
Length a, b, c (Å)56.139, 80.536, 149.505
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: 1669.593 Da / Num. of mol.: 1 / Source method: obtained synthetically / Details: Phosphorylated residues: pSer-892, pTyr-896 / 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.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 124 / 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: 2.46 Å3/Da / Density % sol: 50.07 % / Description: rhomboid shaped crystals
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 5.5
Details: 10% PEG 20000, 100mM Citrate buffer pH 5.5, EDTA 50mM

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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: 1.48→46.05 Å / Num. obs: 56601 / % possible obs: 99.7 % / Redundancy: 13.3 % / CC1/2: 0.999 / Rmerge(I) obs: 0.041 / Rpim(I) all: 0.012 / Rrim(I) all: 0.042 / Net I/σ(I): 26.9 / Num. measured all: 754810
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
1.48-1.5113.52.1593705127490.60.5992.2421.599.2
8.11-46.057.40.03325303410.9960.0130.03665.185.7

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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: 1.48→46.05 Å / SU ML: 0.1614 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 19.5554
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1961 1999 3.54 %
Rwork0.1645 54547 -
obs0.1656 56546 99.56 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 39.34 Å2
Refinement stepCycle: LAST / Resolution: 1.48→46.05 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2293 0 6 124 2423
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.012389
X-RAY DIFFRACTIONf_angle_d1.04133237
X-RAY DIFFRACTIONf_chiral_restr0.0886343
X-RAY DIFFRACTIONf_plane_restr0.0068426
X-RAY DIFFRACTIONf_dihedral_angle_d20.1219906
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.48-1.520.32081390.2483806X-RAY DIFFRACTION98.92
1.52-1.560.23041420.21573850X-RAY DIFFRACTION99.4
1.56-1.60.22391410.17613864X-RAY DIFFRACTION99.78
1.6-1.660.21481420.15593854X-RAY DIFFRACTION99.45
1.66-1.710.19481410.14573858X-RAY DIFFRACTION99.7
1.71-1.780.17761420.13723854X-RAY DIFFRACTION99.78
1.78-1.860.17861420.12983901X-RAY DIFFRACTION99.61
1.86-1.960.18421430.13623892X-RAY DIFFRACTION99.73
1.96-2.090.22711410.14623850X-RAY DIFFRACTION99.43
2.09-2.250.17961440.14983936X-RAY DIFFRACTION99.98
2.25-2.470.19891440.16013914X-RAY DIFFRACTION100
2.47-2.830.19861440.1783939X-RAY DIFFRACTION100
2.83-3.570.21231460.17633979X-RAY DIFFRACTION99.98
3.57-46.050.18051480.16454050X-RAY DIFFRACTION98.15

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