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- PDB-6cmp: Closed structure of inactive SHP2 mutant C459E -

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Basic information

Entry
Database: PDB / ID: 6cmp
TitleClosed structure of inactive SHP2 mutant C459E
ComponentsTyrosine-protein phosphatase non-receptor type 11
KeywordsHYDROLASE / protein tyrosine phosphatase / src homology domain 2 / inactive state / inactive mutant
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 / negative regulation of cell adhesion mediated by integrin / 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 / negative regulation of cell adhesion mediated by integrin / STAT5 Activation / Co-inhibition by BTLA / Netrin mediated repulsion signals / cerebellar cortex formation / negative regulation of neutrophil activation / positive regulation of hormone secretion / regulation of protein export from nucleus / positive regulation of ossification / positive regulation of lipopolysaccharide-mediated signaling pathway / Interleukin-37 signaling / hormone metabolic process / Signaling by Leptin / MET activates PTPN11 / Regulation of RUNX1 Expression and Activity / negative regulation of chondrocyte differentiation / face morphogenesis / Signal regulatory protein family interactions / ERBB signaling pathway / platelet formation / Interleukin-20 family signaling / Interleukin-6 signaling / triglyceride metabolic process / organ growth / megakaryocyte development / peptide hormone receptor binding / negative regulation of type I interferon production / PI-3K cascade:FGFR3 / Co-inhibition by CTLA4 / MAPK3 (ERK1) activation / Platelet sensitization by LDL / STAT5 activation downstream of FLT3 ITD mutants / PI-3K cascade:FGFR2 / PI-3K cascade:FGFR4 / PI-3K cascade:FGFR1 / MAPK1 (ERK2) activation / Prolactin receptor signaling / regulation of cell adhesion mediated by integrin / regulation of type I interferon-mediated signaling pathway / PECAM1 interactions / inner ear development / neurotrophin TRK receptor signaling pathway / Bergmann glial cell differentiation / Regulation of IFNA/IFNB signaling / positive regulation of intracellular signal transduction / peptidyl-tyrosine dephosphorylation / platelet-derived growth factor receptor signaling pathway / phosphoprotein phosphatase activity / RET signaling / Interleukin-3, Interleukin-5 and GM-CSF signaling / PI3K Cascade / ephrin receptor signaling pathway / Co-inhibition by PD-1 / fibroblast growth factor receptor signaling pathway / GAB1 signalosome / regulation of protein-containing complex assembly / Activated NTRK2 signals through FRS2 and FRS3 / positive regulation of insulin receptor signaling pathway / Regulation of IFNG signaling / negative regulation of insulin secretion / Signaling by CSF3 (G-CSF) / FRS-mediated FGFR3 signaling / Signaling by FLT3 ITD and TKD mutants / GPVI-mediated activation cascade / cell adhesion molecule binding / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / Tie2 Signaling / FRS-mediated FGFR1 signaling / homeostasis of number of cells within a tissue / negative regulation of T cell proliferation / hormone-mediated signaling pathway / T cell costimulation / FLT3 Signaling / phosphotyrosine residue binding / protein tyrosine phosphatase activity / protein-tyrosine-phosphatase / protein tyrosine phosphatase activity, metal-dependent / histone H2AXY142 phosphatase activity / non-membrane spanning protein tyrosine phosphatase activity / Downstream signal transduction / positive regulation of mitotic cell cycle / cellular response to epidermal growth factor stimulus / axonogenesis / positive regulation of interferon-beta production / protein tyrosine kinase binding / DNA damage checkpoint signaling / Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE) / integrin-mediated signaling pathway / positive regulation of D-glucose import / Negative regulation of FGFR3 signaling / insulin receptor binding / Negative regulation of FGFR2 signaling / Negative regulation of FGFR4 signaling
Similarity search - Function
Protein-tyrosine phosphatase, non-receptor type-6, -11 / SH2 domain / SHC Adaptor Protein / 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 / Protein-tyrosine phosphatase, catalytic ...Protein-tyrosine phosphatase, non-receptor type-6, -11 / SH2 domain / SHC Adaptor Protein / 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 / 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 / SH2 domain / Src homology 2 (SH2) domain profile. / Src homology 2 domains / SH2 domain / SH2 domain superfamily / Alpha-Beta Complex / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
Tyrosine-protein phosphatase non-receptor type 11
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsPadua, R.A.P. / Sun, Y. / Marko, I. / Pitsawong, W. / Kern, D.
Funding support Brazil, United States, 3items
OrganizationGrant numberCountry
Brazilian National Council for Scientific and Technological Development (CNPq)233809/2014-7 Brazil
Howard Hughes Medical Institute (HHMI) United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM100966 United States
CitationJournal: Nat Commun / Year: 2018
Title: Mechanism of activating mutations and allosteric drug inhibition of the phosphatase SHP2.
Authors: Padua, R.A.P. / Sun, Y. / Marko, I. / Pitsawong, W. / Stiller, J.B. / Otten, R. / Kern, D.
History
DepositionMar 6, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 14, 2018Provider: repository / Type: Initial release
Revision 1.1Feb 20, 2019Group: Author supporting evidence / Data collection / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.2Apr 17, 2019Group: Author supporting evidence / Data collection / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Nov 20, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.4Jan 8, 2020Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.5Oct 4, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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: Tyrosine-protein phosphatase non-receptor type 11


Theoretical massNumber of molelcules
Total (without water)122,0622
Polymers122,0622
Non-polymers00
Water13,745763
1
A: Tyrosine-protein phosphatase non-receptor type 11


Theoretical massNumber of molelcules
Total (without water)61,0311
Polymers61,0311
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Tyrosine-protein phosphatase non-receptor type 11


Theoretical massNumber of molelcules
Total (without water)61,0311
Polymers61,0311
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)54.750, 84.910, 211.920
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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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: 61030.789 Da / Num. of mol.: 2 / Mutation: C459E
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PTPN11, PTP2C, SHPTP2 / Plasmid: pET28a / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3) / References: UniProt: Q06124, protein-tyrosine-phosphatase
#2: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 763 / Source method: isolated from a natural source / Formula: H2O

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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: 2.16 Å3/Da / Density % sol: 39.04 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop / Details: 200 mM lithium nitrate, 20% PEG 3,350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 8.2.1 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Dec 8, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.8→84.91 Å / Num. obs: 91640 / % possible obs: 99.4 % / Redundancy: 6.6 % / Biso Wilson estimate: 25.87 Å2 / CC1/2: 0.994 / Rmerge(I) obs: 0.1599 / Rpim(I) all: 0.06644 / Net I/σ(I): 7.3
Reflection shellResolution: 1.8→1.83 Å / Num. unique obs: 4202 / CC1/2: 0.214 / Rpim(I) all: 1.224 / % possible all: 93.9

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Processing

Software
NameVersionClassification
Blu-Icedata collection
iMOSFLMdata reduction
Aimlessdata scaling
PHASERphasing
Cootmodel building
PHENIX1.13_2998refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4dgp

4dgp


Resolution: 1.8→53 Å / SU ML: 0.2975 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 26.2947
RfactorNum. reflection% reflection
Rfree0.2306 1996 2.19 %
Rwork0.2012 --
obs0.2019 91347 99.22 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso mean: 34.52 Å2
Refinement stepCycle: LAST / Resolution: 1.8→53 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7798 0 0 764 8562
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00388061
X-RAY DIFFRACTIONf_angle_d0.617510920
X-RAY DIFFRACTIONf_chiral_restr0.04691188
X-RAY DIFFRACTIONf_plane_restr0.00331431
X-RAY DIFFRACTIONf_dihedral_angle_d11.33074803
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.8-1.850.45451300.40115875X-RAY DIFFRACTION92.71
1.85-1.90.38191390.36216203X-RAY DIFFRACTION97.79
1.9-1.950.35531410.30496310X-RAY DIFFRACTION99.26
1.95-2.020.29251420.2676345X-RAY DIFFRACTION99.88
2.02-2.090.27631410.23726340X-RAY DIFFRACTION99.98
2.09-2.170.2551430.22066395X-RAY DIFFRACTION99.97
2.17-2.270.24911430.20616378X-RAY DIFFRACTION100
2.27-2.390.26151420.19826401X-RAY DIFFRACTION99.98
2.39-2.540.2291430.18656377X-RAY DIFFRACTION99.97
2.54-2.740.22751440.19316479X-RAY DIFFRACTION99.98
2.74-3.010.25181440.19926439X-RAY DIFFRACTION99.97
3.01-3.450.21221450.18156462X-RAY DIFFRACTION99.98
3.45-4.340.18751460.15736551X-RAY DIFFRACTION99.97
4.34-530.17841530.18496796X-RAY DIFFRACTION99.58

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