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- PDB-6bn5: Non-receptor Protein Tyrosine Phosphatase SHP2 F285S in Complex w... -

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Basic information

Entry
Database: PDB / ID: 6bn5
TitleNon-receptor Protein Tyrosine Phosphatase SHP2 F285S in Complex with Allosteric Inhibitor JLR-2
ComponentsTyrosine-protein phosphatase non-receptor type 11
KeywordsHYDROLASE/HYDROLASE INHIBITOR / SHP2 / PTPN11 / protein tyrosine phosphatase / phosphatase / allosteric inhibitor / HYDROLASE-HYDROLASE INHIBITOR complex
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 / Netrin mediated repulsion signals / positive regulation of hormone secretion ...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 / Netrin mediated repulsion signals / positive regulation of hormone secretion / cerebellar cortex formation / multicellular organismal reproductive process / regulation of protein export from nucleus / positive regulation of ossification / hormone metabolic process / Interleukin-37 signaling / Signaling by Leptin / negative regulation of chondrocyte differentiation / MET activates PTPN11 / Regulation of RUNX1 Expression and Activity / face morphogenesis / ERBB signaling pathway / Costimulation by the CD28 family / Signal regulatory protein family interactions / peptide hormone receptor binding / negative regulation of type I interferon production / platelet formation / megakaryocyte development / organ growth / triglyceride metabolic process / CTLA4 inhibitory signaling / Platelet sensitization by LDL / Interleukin-20 family signaling / PI-3K cascade:FGFR3 / Interleukin-6 signaling / STAT5 activation downstream of FLT3 ITD mutants / PI-3K cascade:FGFR2 / PI-3K cascade:FGFR4 / Prolactin receptor signaling / PI-3K cascade:FGFR1 / MAPK3 (ERK1) activation / MAPK1 (ERK2) activation / PECAM1 interactions / Bergmann glial cell differentiation / regulation of cell adhesion mediated by integrin / regulation of type I interferon-mediated signaling pathway / phosphoprotein phosphatase activity / inner ear development / neurotrophin TRK receptor signaling pathway / platelet-derived growth factor receptor signaling pathway / non-membrane spanning protein tyrosine phosphatase activity / RET signaling / peptidyl-tyrosine dephosphorylation / Interleukin-3, Interleukin-5 and GM-CSF signaling / Regulation of IFNA/IFNB signaling / PI3K Cascade / PD-1 signaling / regulation of protein-containing complex assembly / ephrin receptor signaling pathway / fibroblast growth factor receptor signaling pathway / GAB1 signalosome / Activated NTRK2 signals through FRS2 and FRS3 / negative regulation of insulin secretion / Regulation of IFNG signaling / positive regulation of insulin receptor signaling pathway / FRS-mediated FGFR3 signaling / Signaling by CSF3 (G-CSF) / Signaling by FLT3 ITD and TKD mutants / homeostasis of number of cells within a tissue / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / Tie2 Signaling / FRS-mediated FGFR1 signaling / cellular response to epidermal growth factor stimulus / cell adhesion molecule binding / GPVI-mediated activation cascade / T cell costimulation / FLT3 Signaling / positive regulation of interferon-beta production / hormone-mediated signaling pathway / phosphotyrosine residue binding / positive regulation of mitotic cell cycle / Downstream signal transduction / protein dephosphorylation / Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE) / protein-tyrosine-phosphatase / axonogenesis / protein tyrosine kinase binding / DNA damage checkpoint signaling / protein tyrosine phosphatase activity / integrin-mediated signaling pathway / positive regulation of glucose import / Negative regulation of FGFR3 signaling / Negative regulation of FGFR2 signaling / Negative regulation of FGFR4 signaling / Negative regulation of FGFR1 signaling / Spry regulation of FGF signaling / insulin receptor binding / epidermal growth factor receptor signaling pathway / multicellular organism growth
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
Chem-DZJ / Tyrosine-protein phosphatase non-receptor type 11
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.22 Å
AuthorsBlacklow, S.C. / Stams, T. / Fodor, M. / LaRochelle, J.R.
Funding support United States, 1items
OrganizationGrant numberCountry
Novartis-Dana Farber Cancer Institute Drug Development ProgramP50 GM10718A1 United States
CitationJournal: Bioorg. Med. Chem. / Year: 2017
Title: Identification of an allosteric benzothiazolopyrimidone inhibitor of the oncogenic protein tyrosine phosphatase SHP2.
Authors: LaRochelle, J.R. / Fodor, M. / Ellegast, J.M. / Liu, X. / Vemulapalli, V. / Mohseni, M. / Stams, T. / Buhrlage, S.J. / Stegmaier, K. / LaMarche, M.J. / Acker, M.G. / Blacklow, S.C.
History
DepositionNov 16, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 13, 2017Provider: repository / Type: Initial release
Revision 1.1Oct 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 / software
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _software.name

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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)121,2354
Polymers120,5502
Non-polymers6862
Water3,441191
1
A: Tyrosine-protein phosphatase non-receptor type 11
hetero molecules


Theoretical massNumber of molelcules
Total (without water)60,6182
Polymers60,2751
Non-polymers3431
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)60,6182
Polymers60,2751
Non-polymers3431
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)46.190, 212.234, 55.472
Angle α, β, γ (deg.)90.00, 96.23, 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: 60274.941 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-DZJ / 3-benzyl-8-chloro-2-hydroxy-4H-pyrimido[2,1-b][1,3]benzothiazol-4-one


Mass: 342.799 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C17H11ClN2O2S / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 191 / 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: 2.24 Å3/Da / Density % sol: 45.14 %
Crystal growTemperature: 298.15 K / Method: vapor diffusion, hanging drop / pH: 8.6 / Details: 100 mM Tris pH 8.6, 20% PEG 3350, 1 mM TCEP

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 16, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.218→212.234 Å / Num. obs: 48700 / % possible obs: 93.2 % / Redundancy: 3.2 % / Biso Wilson estimate: 44.98 Å2 / Rmerge(I) obs: 0.161 / Net I/σ(I): 7.1
Reflection shellResolution: 2.218→2.225 Å / Redundancy: 2.8 % / Rmerge(I) obs: 0.79 / Mean I/σ(I) obs: 2 / Num. unique obs: 519 / CC1/2: 0.633 / % possible all: 96.3

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Processing

Software
NameVersionClassification
BUSTER2.11.6refinement
XDSdata reduction
autoPROCdata scaling
BUSTERphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 5I6V

5i6v


Resolution: 2.22→22.38 Å / Cor.coef. Fo:Fc: 0.8854 / Cor.coef. Fo:Fc free: 0.8447 / SU R Cruickshank DPI: 0.349 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.329 / SU Rfree Blow DPI: 0.254 / SU Rfree Cruickshank DPI: 0.263
RfactorNum. reflection% reflectionSelection details
Rfree0.2917 2413 5.04 %RANDOM
Rwork0.236 ---
obs0.2389 47898 91.97 %-
Displacement parametersBiso mean: 45.16 Å2
Baniso -1Baniso -2Baniso -3
1--14.4383 Å20 Å21.0764 Å2
2--10.0254 Å20 Å2
3---4.4129 Å2
Refine analyzeLuzzati coordinate error obs: 0.364 Å
Refinement stepCycle: 1 / Resolution: 2.22→22.38 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7280 0 46 191 7517
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.017473HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.1210071HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d2637SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes197HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1055HARMONIC5
X-RAY DIFFRACTIONt_it7473HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.16
X-RAY DIFFRACTIONt_other_torsion21.03
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion935SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact8290SEMIHARMONIC4
LS refinement shellResolution: 2.22→2.28 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2795 112 5.2 %
Rwork0.2519 2043 -
all0.2534 2155 -
obs--56.64 %

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