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- PDB-9qa5: Structure of the N-SH2 domain of SHP2 in complex with the phospho... -

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Basic information

Entry
Database: PDB / ID: 9qa5
TitleStructure of the N-SH2 domain of SHP2 in complex with the phosphoY627-Gab1 (613-651) peptide
Components
  • GRB2-associated-binding protein 1
  • Isoform 3 of Tyrosine-protein phosphatase non-receptor type 11
KeywordsSIGNALING PROTEIN / SH2-domain / phosphatase / PTPN11 / phospho-tyrosine
Function / homology
Function and homology information


negative regulation of cortisol secretion / intestinal epithelial cell migration / microvillus organization / negative regulation of growth hormone secretion / genitalia development / atrioventricular canal development / endothelial cell chemotaxis / STAT5 Activation / Co-inhibition by BTLA / Netrin mediated repulsion signals ...negative regulation of cortisol secretion / intestinal epithelial cell migration / microvillus organization / negative regulation of growth hormone secretion / genitalia development / atrioventricular canal development / endothelial cell chemotaxis / STAT5 Activation / Co-inhibition by BTLA / Netrin mediated repulsion signals / negative regulation of neutrophil activation / cerebellar cortex formation / Activated NTRK2 signals through PI3K / MET receptor recycling / positive regulation of hormone secretion / 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 / hormone metabolic process / MET activates RAP1 and RAC1 / negative regulation of chondrocyte differentiation / Regulation of RUNX1 Expression and Activity / MET activates PI3K/AKT signaling / Signal regulatory protein family interactions / face morphogenesis / vascular endothelial growth factor signaling pathway / platelet formation / ERBB signaling pathway / triglyceride metabolic process / organ growth / megakaryocyte development / Interleukin-20 family signaling / Interleukin-6 signaling / regulation of cell adhesion mediated by integrin / Erythropoietin activates Phosphoinositide-3-kinase (PI3K) / 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 / 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 events in ERBB2 signaling / PI3K Cascade / positive regulation of blood vessel endothelial cell migration / Co-inhibition by PD-1 / fibroblast growth factor receptor signaling pathway / positive regulation of insulin receptor signaling pathway / ephrin receptor signaling pathway / GAB1 signalosome / regulation of protein-containing complex assembly / Regulation of IFNG signaling / Activated NTRK2 signals through FRS2 and FRS3 / Signaling by FGFR4 in disease / 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 / Signaling by FGFR3 in disease / Tie2 Signaling / phosphoprotein phosphatase activity / Signaling by FGFR2 in disease / phosphotyrosine residue binding / hormone-mediated signaling pathway / protein-tyrosine-phosphatase / cell adhesion molecule binding / FLT3 Signaling / Signaling by FGFR1 in disease / signaling adaptor activity / homeostasis of number of cells within a tissue / Downstream signal transduction / positive regulation of mitotic cell cycle / protein tyrosine phosphatase activity / axonogenesis
Similarity search - Function
GRB2-associated-binding protein 1-4-like / Protein-tyrosine phosphatase, non-receptor type-6, -11 / 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. ...GRB2-associated-binding protein 1-4-like / Protein-tyrosine phosphatase, non-receptor type-6, -11 / 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
Similarity search - Domain/homology
Tyrosine-protein phosphatase non-receptor type 11 / GRB2-associated-binding protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.08 Å
AuthorsMachner, L. / Breithaupt, C. / Kniest, J. / Parthier, C. / Feller, S.M. / Stubbs, M.T.
Funding support Germany, 1items
OrganizationGrant numberCountry
German Research Foundation (DFG) Germany
CitationJournal: Structure / Year: 2025
Title: Mechanism of SHP2 activation by bis-Tyr-phosphorylated Gab1.
Authors: Lisa Machner / Alaa Shaikhqasem / Tobias Gruber / Farzad Hamdi / Constanze Breithaupt / Judith Kniest / Felix Wiebe / Marc Lewitzky / Christoph Parthier / Fotis L Kyrilis / Jochen Balbach / ...Authors: Lisa Machner / Alaa Shaikhqasem / Tobias Gruber / Farzad Hamdi / Constanze Breithaupt / Judith Kniest / Felix Wiebe / Marc Lewitzky / Christoph Parthier / Fotis L Kyrilis / Jochen Balbach / Panagiotis L Kastritis / Stephan M Feller / Milton T Stubbs /
Abstract: The non-receptor tyrosine phosphatase SHP2 (SH2 domain-containing protein tyrosine phosphatase 2) (PTPN11) is a regulator of diverse cellular functions including mitogenic activation and cell ...The non-receptor tyrosine phosphatase SHP2 (SH2 domain-containing protein tyrosine phosphatase 2) (PTPN11) is a regulator of diverse cellular functions including mitogenic activation and cell migration. It comprises two tandem Src-homology 2 (SH2) domains followed by the catalytic domain and is autoinhibited by the N-terminal SH2 domain blocking access to the active site. Mutations influencing auto-inhibition have been implicated in cancer and other diseases, and allosteric inhibitors have been developed that stabilize the inactive state. Here, we show that the intrinsically disordered bis-phosphorylated SHP2-activating peptide pYpY-Gab1 binds to both SH2 domains, undergoing partial ordering in the process. In addition to eliciting changes in SH2 domain dynamics, the peptide reorganizes their relative orientations to generate a new SH2-SH2 interface. Our data suggest an active conformation for SHP2 that is also applicable to the hematopoietic cell-specific SHP1 (PTPN6), shedding light on the activation mechanism of both enzymes and paving the way for the development of novel compounds to modulate SHP2 activity.
History
DepositionFeb 27, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 31, 2025Provider: repository / Type: Initial release
Revision 1.1Jan 7, 2026Group: Database references / Category: citation / Item: _citation.pdbx_database_id_PubMed / _citation.title

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Structure visualization

Structure viewerMolecule:
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Assembly

Deposited unit
A: Isoform 3 of Tyrosine-protein phosphatase non-receptor type 11
B: GRB2-associated-binding protein 1


Theoretical massNumber of molelcules
Total (without water)16,2302
Polymers16,2302
Non-polymers00
Water77543
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: isothermal titration calorimetry
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1410 Å2
ΔGint-17 kcal/mol
Surface area5860 Å2
Unit cell
Length a, b, c (Å)60.780, 60.780, 69.847
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number96
Space group name H-MP43212
Space group name HallP4nw2abw
Symmetry operation#1: x,y,z
#2: -y+1/2,x+1/2,z+3/4
#3: y+1/2,-x+1/2,z+1/4
#4: x+1/2,-y+1/2,-z+1/4
#5: -x+1/2,y+1/2,-z+3/4
#6: -x,-y,z+1/2
#7: y,x,-z
#8: -y,-x,-z+1/2
Components on special symmetry positions
IDModelComponents
11A-238-

HOH

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Components

#1: Protein Isoform 3 of 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: 12006.469 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 GRB2-associated-binding protein 1 / GRB2-associated binder 1 / Growth factor receptor bound protein 2-associated protein 1


Mass: 4223.590 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: Q13480
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 43 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
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: 1.99 Å3/Da / Density % sol: 38.11 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: 5 % PEG3350, 0.2 M NaCl, 0.1 M BisTris, pH 5.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 / Wavelength: 1.5418 Å
DetectorType: RIGAKU HyPix-Arc 150 / Detector: PIXEL / Date: Jan 14, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.08→69.85 Å / Num. obs: 8364 / % possible obs: 100 % / Redundancy: 14.2 % / Biso Wilson estimate: 31.76 Å2 / CC1/2: 0.998 / Rrim(I) all: 0.137 / Net I/σ(I): 14
Reflection shellResolution: 2.08→2.14 Å / Redundancy: 13.3 % / Mean I/σ(I) obs: 2.9 / Num. unique obs: 633 / CC1/2: 0.817 / Rrim(I) all: 0.95 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX1.21.1_5286refinement
XDSVERSION Jan 31, 2020 BUILT=20200417data reduction
Aimless0.7.4data scaling
PHASER2.8.3phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.08→27.87 Å / SU ML: 0.2609 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 30.8407
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2729 405 4.88 %
Rwork0.2258 7890 -
obs0.2281 8295 99.7 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 36.2 Å2
Refinement stepCycle: LAST / Resolution: 2.08→27.87 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms870 0 0 43 913
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0061898
X-RAY DIFFRACTIONf_angle_d0.95021218
X-RAY DIFFRACTIONf_chiral_restr0.0499130
X-RAY DIFFRACTIONf_plane_restr0.0071158
X-RAY DIFFRACTIONf_dihedral_angle_d15.794337
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.08-2.380.31811420.24622569X-RAY DIFFRACTION100
2.38-30.37411270.28042591X-RAY DIFFRACTION99.74
3-27.870.23281360.20212730X-RAY DIFFRACTION99.38

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