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- PDB-7jvm: Non-receptor Protein Tyrosine Phosphatase SHP2 in Complex with Al... -

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Basic information

Entry
Database: PDB / ID: 7jvm
TitleNon-receptor Protein Tyrosine Phosphatase SHP2 in Complex with Allosteric Inhibitor TNO155
ComponentsTyrosine-protein phosphatase non-receptor type 11
KeywordsHYDROLASE/HYDROLASE INHIBITOR / PHOSPHATASE PTP / INHIBITOR / PTPN11 / ALLOSTERIC / SHP2 / HYDROLASE / 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 / phosphoprotein phosphatase activity / Bergmann glial cell differentiation / regulation of cell adhesion mediated by integrin / regulation of type I interferon-mediated signaling pathway / neurotrophin TRK receptor signaling pathway / inner ear development / 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 / PI3K Cascade / Regulation of IFNA/IFNB signaling / PD-1 signaling / negative regulation of insulin secretion / 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 / 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 / FRS-mediated FGFR1 signaling / GPVI-mediated activation cascade / cell adhesion molecule binding / cellular response to epidermal growth factor stimulus / Tie2 Signaling / 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 / axonogenesis / protein dephosphorylation / Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE) / protein tyrosine kinase binding / protein-tyrosine-phosphatase / 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 / brain development / insulin receptor binding / epidermal growth factor receptor signaling pathway
Similarity search - Function
Protein-tyrosine phosphatase, non-receptor type-6, -11 / 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 ...Protein-tyrosine phosphatase, non-receptor type-6, -11 / 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
Similarity search - Domain/homology
PHOSPHATE ION / Chem-VKS / Tyrosine-protein phosphatase non-receptor type 11
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.166 Å
AuthorsFodor, M. / Stams, T.
CitationJournal: J.Med.Chem. / Year: 2020
Title: Identification of TNO155, an Allosteric SHP2 Inhibitor for the Treatment of Cancer.
Authors: LaMarche, M.J. / Acker, M. / Argintaru, A. / Bauer, D. / Boisclair, J. / Chan, H. / Chen, C.H. / Chen, Y.N. / Chen, Z. / Deng, Z. / Dore, M. / Dunstan, D. / Fan, J. / Fekkes, P. / Firestone, ...Authors: LaMarche, M.J. / Acker, M. / Argintaru, A. / Bauer, D. / Boisclair, J. / Chan, H. / Chen, C.H. / Chen, Y.N. / Chen, Z. / Deng, Z. / Dore, M. / Dunstan, D. / Fan, J. / Fekkes, P. / Firestone, B. / Fodor, M. / Garcia-Fortanet, J. / Fortin, P.D. / Fridrich, C. / Giraldes, J. / Glick, M. / Grunenfelder, D. / Hao, H.X. / Hentemann, M. / Ho, S. / Jouk, A. / Kang, Z.B. / Karki, R. / Kato, M. / Keen, N. / Koenig, R. / LaBonte, L.R. / Larrow, J. / Liu, G. / Liu, S. / Majumdar, D. / Mathieu, S. / Meyer, M.J. / Mohseni, M. / Ntaganda, R. / Palermo, M. / Perez, L. / Pu, M. / Ramsey, T. / Reilly, J. / Sarver, P. / Sellers, W.R. / Sendzik, M. / Shultz, M.D. / Slisz, J. / Slocum, K. / Smith, T. / Spence, S. / Stams, T. / Straub, C. / Tamez Jr., V. / Toure, B.B. / Towler, C. / Wang, P. / Wang, H. / Williams, S.L. / Yang, F. / Yu, B. / Zhang, J.H. / Zhu, S.
History
DepositionAug 21, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 23, 2020Provider: repository / Type: Initial release
Revision 1.1Dec 9, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.name
Revision 1.2Oct 18, 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)121,91010
Polymers120,4962
Non-polymers1,4148
Water6,323351
1
A: Tyrosine-protein phosphatase non-receptor type 11
hetero molecules


Theoretical massNumber of molelcules
Total (without water)60,9555
Polymers60,2481
Non-polymers7074
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)60,9555
Polymers60,2481
Non-polymers7074
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)46.292, 212.561, 55.752
Angle α, β, γ (deg.)90.000, 96.720, 90.000
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: 60247.957 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-VKS / (3S,4S)-8-{6-amino-5-[(2-amino-3-chloropyridin-4-yl)sulfanyl]pyrazin-2-yl}-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine


Mass: 421.947 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H24ClN7OS / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-PO4 / PHOSPHATE ION / Phosphate


Mass: 94.971 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: PO4
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 351 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.45 Å3/Da / Density % sol: 49.83 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, sitting drop / Details: 17% PEG 3350 and 200 mM ammonium phosphate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Mar 4, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.166→106.28 Å / Num. obs: 54438 / % possible obs: 96.1 % / Redundancy: 3.3 % / Biso Wilson estimate: 39.65 Å2 / CC1/2: 0.994 / Rmerge(I) obs: 0.108 / Net I/σ(I): 8.4
Reflection shellResolution: 2.166→2.173 Å / Redundancy: 3.1 % / Rmerge(I) obs: 0.642 / Mean I/σ(I) obs: 2.1 / Num. unique obs: 549 / CC1/2: 0.708 / % possible all: 99.5

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Processing

Software
NameVersionClassification
BUSTER2.11.7 (19-MAR-2020)refinement
XSCALEdata scaling
PDB_EXTRACT3.25data extraction
XDSdata reduction
BUSTERphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 2shp

2shp


Resolution: 2.166→106.28 Å / Cor.coef. Fo:Fc: 0.931 / Cor.coef. Fo:Fc free: 0.902 / SU R Cruickshank DPI: 0.262 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.255 / SU Rfree Blow DPI: 0.197 / SU Rfree Cruickshank DPI: 0.201
RfactorNum. reflection% reflectionSelection details
Rfree0.2356 2680 4.93 %RANDOM
Rwork0.1922 ---
obs0.1943 54385 96 %-
Displacement parametersBiso max: 83.68 Å2 / Biso mean: 36.33 Å2 / Biso min: 10.23 Å2
Baniso -1Baniso -2Baniso -3
1--3.2974 Å20 Å20.7323 Å2
2--0.3963 Å20 Å2
3---2.9011 Å2
Refine analyzeLuzzati coordinate error obs: 0.28 Å
Refinement stepCycle: final / Resolution: 2.166→106.28 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7813 0 86 352 8251
Biso mean--41.97 38.8 -
Num. residues----965
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d2880SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes1361HARMONIC5
X-RAY DIFFRACTIONt_it8062HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion1009SEMIHARMONIC5
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_contact6744SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d8062HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg10883HARMONIC20.96
X-RAY DIFFRACTIONt_omega_torsion3.17
X-RAY DIFFRACTIONt_other_torsion18.45
LS refinement shellResolution: 2.17→2.18 Å / Rfactor Rfree error: 0 / Total num. of bins used: 51
RfactorNum. reflection% reflection
Rfree0.3016 48 4.41 %
Rwork0.239 1040 -
all0.2418 1088 -
obs--99.9 %

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