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- PDB-6md9: NON-RECEPTOR PROTEIN TYROSINE PHOSPHATASE SHP2 IN COMPLEX WITH AL... -

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Basic information

Entry
Database: PDB / ID: 6md9
TitleNON-RECEPTOR PROTEIN TYROSINE PHOSPHATASE SHP2 IN COMPLEX WITH ALLOSTERIC INHIBITOR Isoxazolo-pyridinone 3
ComponentsTyrosine-protein phosphatase non-receptor type 11
KeywordsHYDROLASE/HYDROLASE INHIBITOR / SHP2 / PTPN11 / PROTEIN TYROSINE PHOSPHATASE / PHOSPHATASE / ALLOSTERIC INHIBITOR / HYDROLASE-HYDROLASE INHIBITOR COMPLEX / HYDROLASE
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 / negative regulation of neutrophil activation / cerebellar cortex formation / positive regulation of hormone secretion / 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 / hormone metabolic process / Regulation of RUNX1 Expression and Activity / negative regulation of chondrocyte differentiation / Signal regulatory protein family interactions / face morphogenesis / ERBB signaling pathway / platelet formation / triglyceride metabolic process / megakaryocyte development / negative regulation of type I interferon production / organ growth / 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 / PI-3K cascade:FGFR4 / MAPK3 (ERK1) activation / PI-3K cascade:FGFR1 / 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 / inner ear development / Bergmann glial cell differentiation / 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 / fibroblast growth factor receptor signaling pathway / positive regulation of insulin receptor signaling pathway / GAB1 signalosome / ephrin receptor signaling pathway / regulation of protein-containing complex assembly / Regulation of IFNG signaling / Activated NTRK2 signals through FRS2 and FRS3 / GPVI-mediated activation cascade / Signaling by CSF3 (G-CSF) / FRS-mediated FGFR3 signaling / negative regulation of T cell proliferation / cell adhesion molecule binding / Signaling by FLT3 ITD and TKD mutants / T cell costimulation / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / hormone-mediated signaling pathway / FRS-mediated FGFR1 signaling / Tie2 Signaling / phosphotyrosine residue binding / protein-tyrosine-phosphatase / FLT3 Signaling / homeostasis of number of cells within a tissue / Downstream signal transduction / positive regulation of mitotic cell cycle / axonogenesis / protein tyrosine phosphatase activity / positive regulation of interferon-beta production / protein tyrosine kinase binding / DNA damage checkpoint signaling / cellular response to epidermal growth factor stimulus / Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE) / integrin-mediated signaling pathway / positive regulation of D-glucose import / insulin receptor binding / 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 / negative regulation of insulin secretion
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 profile. / Tyrosine-specific protein phosphatases domain / 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-JEJ / PHOSPHATE ION / Tyrosine-protein phosphatase non-receptor type 11
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.12 Å
AuthorsFodor, M. / Stams, T.
CitationJournal: J. Med. Chem. / Year: 2019
Title: Optimization of Fused Bicyclic Allosteric SHP2 Inhibitors.
Authors: Bagdanoff, J.T. / Chen, Z. / Acker, M. / Chen, Y.N. / Chan, H. / Dore, M. / Firestone, B. / Fodor, M. / Fortanet, J. / Hentemann, M. / Kato, M. / Koenig, R. / LaBonte, L.R. / Liu, S. / ...Authors: Bagdanoff, J.T. / Chen, Z. / Acker, M. / Chen, Y.N. / Chan, H. / Dore, M. / Firestone, B. / Fodor, M. / Fortanet, J. / Hentemann, M. / Kato, M. / Koenig, R. / LaBonte, L.R. / Liu, S. / Mohseni, M. / Ntaganda, R. / Sarver, P. / Smith, T. / Sendzik, M. / Stams, T. / Spence, S. / Towler, C. / Wang, H. / Wang, P. / Williams, S.L. / LaMarche, M.J.
History
DepositionSep 4, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 13, 2019Provider: repository / Type: Initial release
Revision 1.1Mar 13, 2019Group: Data collection / Database references / Category: citation / citation_author / pdbx_database_proc
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.name
Revision 1.2Sep 25, 2019Group: Data collection / Refinement description
Category: refine / refine_ls_shell ...refine / refine_ls_shell / reflns / reflns_shell
Item: _refine.ls_R_factor_R_free / _refine.ls_R_factor_R_work ..._refine.ls_R_factor_R_free / _refine.ls_R_factor_R_work / _refine.pdbx_starting_model / _reflns.pdbx_Rmerge_I_obs / _reflns_shell.Rmerge_I_obs / _reflns_shell.meanI_over_sigI_obs / _reflns_shell.pdbx_redundancy / _reflns_shell.percent_possible_all
Revision 1.3Oct 11, 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)121,7437
Polymers120,6702
Non-polymers1,0735
Water11,908661
1
A: Tyrosine-protein phosphatase non-receptor type 11
hetero molecules


Theoretical massNumber of molelcules
Total (without water)60,8243
Polymers60,3351
Non-polymers4892
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Tyrosine-protein phosphatase non-receptor type 11
hetero molecules


Theoretical massNumber of molelcules
Total (without water)60,9194
Polymers60,3351
Non-polymers5843
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)46.340, 213.960, 55.830
Angle α, β, γ (deg.)90.000, 96.690, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z

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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: 60335.035 Da / Num. of mol.: 2
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-JEJ / 3-(2-chlorophenyl)-6-{4-[(dimethylamino)methyl]phenyl}-5-methyl[1,2]oxazolo[4,5-c]pyridin-4(5H)-one


Mass: 393.866 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H20ClN3O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: PO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 661 / 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: 2.28 Å3/Da / Density % sol: 46.01 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / Details: 17% PEG3350, 200MM AMMONIUM PHOSPHATE

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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: May 31, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.12→213.96 Å / Num. obs: 60227 / % possible obs: 99.5 % / Redundancy: 3.4 % / Rmerge(I) obs: 0.104 / Net I/σ(I): 9.4
Reflection shellResolution: 2.12→2.13 Å / Redundancy: 3.5 % / Rmerge(I) obs: 0.561 / Mean I/σ(I) obs: 2.6 / % possible all: 99.7

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Processing

Software
NameClassification
BUSTERrefinement
XDSdata reduction
autoPROCdata scaling
BUSTERphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: PDB entry 2SHP

2shp


Resolution: 2.12→21.4 Å / Cross valid method: FREE R-VALUE
RfactorNum. reflection% reflection
Rfree0.272 --
Rwork0.218 --
obs-60103 99.4 %
Refinement stepCycle: LAST / Resolution: 2.12→21.4 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7616 0 71 661 8348
LS refinement shellHighest resolution: 2.12 Å / Rfactor Rfree: 0.299 / Rfactor Rwork: 0.237

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