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- PDB-5i6v: Structure of F285S, a Cancer-Associated Mutation of the Oncogenic... -

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Basic information

Entry
Database: PDB / ID: 5i6v
TitleStructure of F285S, a Cancer-Associated Mutation of the Oncogenic Phosphatase SHP2
ComponentsTyrosine-protein phosphatase non-receptor type 11
KeywordsHYDROLASE / SHP2 / Cancer-Associated Mutation / Inhibitors
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 / multicellular organismal reproductive process / atrioventricular canal development / negative regulation of cell adhesion mediated by integrin / STAT5 Activation / Netrin mediated repulsion signals ...negative regulation of cortisol secretion / intestinal epithelial cell migration / microvillus organization / negative regulation of growth hormone secretion / genitalia development / multicellular organismal reproductive process / atrioventricular canal development / negative regulation of cell adhesion mediated by integrin / STAT5 Activation / Netrin mediated repulsion signals / cerebellar cortex formation / positive regulation of hormone secretion / Interleukin-37 signaling / regulation of protein export from nucleus / positive regulation of ossification / hormone metabolic process / Signaling by Leptin / MET activates PTPN11 / negative regulation of chondrocyte differentiation / Regulation of RUNX1 Expression and Activity / face morphogenesis / Costimulation by the CD28 family / triglyceride metabolic process / ERBB signaling pathway / Signal regulatory protein family interactions / organ growth / platelet formation / megakaryocyte development / negative regulation of type I interferon production / peptide hormone receptor binding / Platelet sensitization by LDL / CTLA4 inhibitory signaling / PI-3K cascade:FGFR2 / Interleukin-20 family signaling / PI-3K cascade:FGFR3 / Interleukin-6 signaling / STAT5 activation downstream of FLT3 ITD mutants / PI-3K cascade:FGFR4 / Prolactin receptor signaling / MAPK3 (ERK1) activation / PI-3K cascade:FGFR1 / PECAM1 interactions / regulation of cell adhesion mediated by integrin / MAPK1 (ERK2) activation / regulation of type I interferon-mediated signaling pathway / Bergmann glial cell differentiation / neurotrophin TRK receptor signaling pathway / inner ear development / phosphoprotein phosphatase activity / platelet-derived growth factor receptor signaling pathway / non-membrane spanning protein tyrosine phosphatase activity / PI3K Cascade / RET signaling / peptidyl-tyrosine dephosphorylation / Interleukin-3, Interleukin-5 and GM-CSF signaling / Regulation of IFNA/IFNB signaling / fibroblast growth factor receptor signaling pathway / regulation of protein-containing complex assembly / ephrin receptor signaling pathway / PD-1 signaling / GAB1 signalosome / Activated NTRK2 signals through FRS2 and FRS3 / negative regulation of insulin secretion / Regulation of IFNG signaling / Signaling by CSF3 (G-CSF) / positive regulation of insulin receptor signaling pathway / cell adhesion molecule binding / FRS-mediated FGFR2 signaling / FRS-mediated FGFR3 signaling / Signaling by FLT3 ITD and TKD mutants / FRS-mediated FGFR4 signaling / homeostasis of number of cells within a tissue / GPVI-mediated activation cascade / Tie2 Signaling / FRS-mediated FGFR1 signaling / FLT3 Signaling / T cell costimulation / cellular response to epidermal growth factor stimulus / phosphotyrosine residue binding / protein dephosphorylation / positive regulation of interferon-beta production / hormone-mediated signaling pathway / protein tyrosine kinase binding / Downstream signal transduction / positive regulation of mitotic cell cycle / axonogenesis / protein-tyrosine-phosphatase / Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE) / protein tyrosine phosphatase activity / DNA damage checkpoint signaling / integrin-mediated signaling pathway / positive regulation of D-glucose import / Negative regulation of FGFR2 signaling / Negative regulation of FGFR3 signaling / Negative regulation of FGFR4 signaling / insulin receptor binding / Negative regulation of FGFR1 signaling / Spry regulation of FGF signaling / brain development / epidermal growth factor receptor signaling pathway
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: 1.87 Å
AuthorsXu, X. / Blacklow, S.C.
Funding support United States, 1items
OrganizationGrant numberCountry
William Lawrence Blanche Hughes FoundationJCA, SCB, KS United States
CitationJournal: Biochemistry / Year: 2016
Title: Structural and Functional Consequences of Three Cancer-Associated Mutations of the Oncogenic Phosphatase SHP2.
Authors: LaRochelle, J.R. / Fodor, M. / Xu, X. / Durzynska, I. / Fan, L. / Stams, T. / Chan, H.M. / LaMarche, M.J. / Chopra, R. / Wang, P. / Fortin, P.D. / Acker, M.G. / Blacklow, S.C.
History
DepositionFeb 16, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 13, 2016Provider: repository / Type: Initial release
Revision 1.1May 4, 2016Group: Database references
Revision 1.2Sep 27, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / citation / database_2 / pdbx_initial_refinement_model / pdbx_struct_oper_list / struct_ref_seq_dif
Item: _citation.journal_id_CSD / _database_2.pdbx_DOI ..._citation.journal_id_CSD / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_oper_list.symmetry_operation / _struct_ref_seq_dif.details

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)120,5604
Polymers120,3762
Non-polymers1842
Water19,9611108
1
A: Tyrosine-protein phosphatase non-receptor type 11


Theoretical massNumber of molelcules
Total (without water)60,1881
Polymers60,1881
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Tyrosine-protein phosphatase non-receptor type 11
hetero molecules


Theoretical massNumber of molelcules
Total (without water)60,3723
Polymers60,1881
Non-polymers1842
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)45.822, 214.263, 55.472
Angle α, β, γ (deg.)90.00, 96.08, 90.00
Int Tables number4
Space group name H-MP1211

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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: 60187.863 Da / Num. of mol.: 2 / Mutation: F285S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PTPN11, PTP2C, SHPTP2 / Production host: Escherichia coli (E. coli) / References: UniProt: Q06124, protein-tyrosine-phosphatase
#2: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1108 / 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: 2.23 Å3/Da / Density % sol: 44.93 %
Crystal growTemperature: 297 K / Method: vapor diffusion / Details: 0.2M Sodium Malonate, pH7.0, 20% w/v PEG3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.9792 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Feb 19, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9792 Å / Relative weight: 1
ReflectionResolution: 1.87→55.16 Å / Num. obs: 86484 / % possible obs: 99.02 % / Redundancy: 2.5 % / CC1/2: 0.971 / Rmerge(I) obs: 0.142 / Net I/σ(I): 8.36
Reflection shellResolution: 1.87→1.937 Å / Redundancy: 2.6 % / Rmerge(I) obs: 0.644 / Mean I/σ(I) obs: 1.65 / % possible all: 98.1

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Processing

Software
NameVersionClassification
PHENIX1.8.4_1496refinement
HKL-2000data reduction
HKL-2000data scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2SHP

2shp


Resolution: 1.87→55.16 Å / SU ML: 0.23 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 23.22 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2317 4329 5.01 %
Rwork0.2014 --
obs0.2029 86466 99 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.87→55.16 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7798 0 12 1108 8918
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0047982
X-RAY DIFFRACTIONf_angle_d0.77810796
X-RAY DIFFRACTIONf_dihedral_angle_d12.8642940
X-RAY DIFFRACTIONf_chiral_restr0.031178
X-RAY DIFFRACTIONf_plane_restr0.0031404
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.87-1.89130.3521370.31012768X-RAY DIFFRACTION97
1.8913-1.91350.32821380.29862737X-RAY DIFFRACTION99
1.9135-1.93680.2911260.29292674X-RAY DIFFRACTION98
1.9368-1.96140.2821570.27212697X-RAY DIFFRACTION98
1.9614-1.98720.34251250.26882776X-RAY DIFFRACTION99
1.9872-2.01440.2981440.24862682X-RAY DIFFRACTION98
2.0144-2.04320.28061430.24192755X-RAY DIFFRACTION99
2.0432-2.07370.29091470.22432695X-RAY DIFFRACTION99
2.0737-2.10610.26761650.21932706X-RAY DIFFRACTION99
2.1061-2.14060.21441340.22632722X-RAY DIFFRACTION98
2.1406-2.17750.25591510.21662755X-RAY DIFFRACTION99
2.1775-2.21710.26651540.22012713X-RAY DIFFRACTION99
2.2171-2.25980.26761520.2162691X-RAY DIFFRACTION99
2.2598-2.30590.29391640.21652743X-RAY DIFFRACTION99
2.3059-2.3560.22031500.22082697X-RAY DIFFRACTION99
2.356-2.41080.2231340.20822801X-RAY DIFFRACTION99
2.4108-2.47110.25351480.21162654X-RAY DIFFRACTION99
2.4711-2.53790.24241380.21142813X-RAY DIFFRACTION99
2.5379-2.61260.22561500.20332709X-RAY DIFFRACTION99
2.6126-2.69690.2761490.21032765X-RAY DIFFRACTION99
2.6969-2.79330.19621290.19862724X-RAY DIFFRACTION99
2.7933-2.90520.26121420.19952776X-RAY DIFFRACTION99
2.9052-3.03740.22981380.19822778X-RAY DIFFRACTION100
3.0374-3.19750.21311520.19432701X-RAY DIFFRACTION100
3.1975-3.39780.20571470.18212790X-RAY DIFFRACTION100
3.3978-3.66010.18541410.16832745X-RAY DIFFRACTION100
3.6601-4.02830.18821240.16512787X-RAY DIFFRACTION100
4.0283-4.6110.17681470.15082773X-RAY DIFFRACTION100
4.611-5.80840.20251520.16392756X-RAY DIFFRACTION100
5.8084-55.18430.19511510.18832754X-RAY DIFFRACTION99
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.15390.57930.13391.19680.02731.01320.053-0.05970.30670.0521-0.0127-0.5631-0.0770.2213-0.02310.0912-0.021-0.03750.1172-0.03990.34216.944215.167-4.9106
20.32570.1278-0.1620.7875-0.57160.6308-0.01340.01440.1447-0.23290.0714-0.2558-0.1272-0.1427-0.01940.2280.00350.05180.08150.00470.19475.720920.4604-20.7909
30.97160.05880.00161.08440.19811.00210.0279-0.09020.36490.10920.0730.1444-0.0803-0.14430.01720.0383-0.0114-0.05120.0746-0.00990.0868-8.95224.6328-3.1428
40.89570.2495-0.32171.0031-0.05320.3597-0.04560.0376-0.0539-0.12710.0194-0.01640.0036-0.0529-0.00080.0474-0.0268-0.03570.07020.01640.0387-9.4281-10.0877-13.2585
51.2578-0.67570.00751.37890.00010.7645-0.00550.1386-0.0533-0.0561-0.0102-0.30290.04170.1493-0.00490.06840.00810.00060.1015-0.030.160813.882954.9269-18.0983
60.3672-0.05940.02081.27450.3380.089-0.1669-0.0749-0.1653-0.0340.2849-0.2416-0.2766-0.09720.0070.49990.02960.01570.14580.00230.14331.359943.0316.6916
70.8806-0.1313-0.04031.1590.04911.2823-0.09210.0632-0.1004-0.13780.03480.00310.0841-0.03250.00320.1329-0.00860.01120.0595-0.01470.0687-8.457362.6012-20.2756
80.6065-0.3190.32371.0331-0.05941.0217-0.0504-0.03610.05260.03650.0308-0.0452-0.0461-0.01770.01450.05020.0038-0.0030.059-0.00160.0503-10.555177.3333-12.0672
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 3 through 56 )
2X-RAY DIFFRACTION2chain 'A' and (resid 57 through 246 )
3X-RAY DIFFRACTION3chain 'A' and (resid 247 through 311 )
4X-RAY DIFFRACTION4chain 'A' and (resid 312 through 525 )
5X-RAY DIFFRACTION5chain 'B' and (resid 2 through 106 )
6X-RAY DIFFRACTION6chain 'B' and (resid 107 through 246 )
7X-RAY DIFFRACTION7chain 'B' and (resid 247 through 326 )
8X-RAY DIFFRACTION8chain 'B' and (resid 327 through 525 )

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