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

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Basic information

Entry
Database: PDB / ID: 7jvn
TitleNon-receptor Protein Tyrosine Phosphatase SHP2 in Complex with Allosteric Inhibitor Compound 24
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 / 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 / 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-VKP / Tyrosine-protein phosphatase non-receptor type 11
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.917 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)121,92911
Polymers120,4962
Non-polymers1,4339
Water13,295738
1
A: Tyrosine-protein phosphatase non-receptor type 11
hetero molecules


Theoretical massNumber of molelcules
Total (without water)61,0126
Polymers60,2481
Non-polymers7645
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)60,9175
Polymers60,2481
Non-polymers6694
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)46.090, 214.736, 55.840
Angle α, β, γ (deg.)90.000, 97.090, 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 natural source / Source: (natural) Homo sapiens (human) / References: UniProt: Q06124, protein-tyrosine-phosphatase
#2: Chemical ChemComp-VKP / 6-(4-amino-4-methylpiperidin-1-yl)-3-[(2,3-dichlorophenyl)sulfanyl]pyrazin-2-amine


Mass: 384.327 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C16H19Cl2N5S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: PO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 738 / 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: 2.27 Å3/Da / Density % sol: 45.9 %
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 PILATUS 6M / Detector: PIXEL / Date: Aug 16, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.917→214.736 Å / Num. obs: 82027 / % possible obs: 99.9 % / Redundancy: 3.4 % / Biso Wilson estimate: 27.46 Å2 / Rpim(I) all: 0.057 / Rrim(I) all: 0.107 / Rsym value: 0.076 / Net I/av σ(I): 8.1 / Net I/σ(I): 9.5 / Num. measured all: 281714
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique obsRpim(I) allRrim(I) allRsym valueNet I/σ(I) obs% possible all
1.92-2.023.50.4751.641194119280.3440.6460.4752.299.9
2.02-2.143.30.2982.637969113360.2230.4140.2983.399.9
2.14-2.293.50.2083.737457106340.1480.2810.2084.9100
2.29-2.473.40.1584.83376798990.1170.2180.1586.299.9
2.47-2.713.40.1136.63143191600.0850.1590.1138.399.9
2.71-3.033.50.0828.92885882040.060.1140.08211.699.9
3.03-3.53.30.05512.32448073180.0420.0780.05516.399.8
3.5-4.293.50.04414.42165461470.0330.0610.04421.899.9
4.29-6.063.40.0415.41601347530.030.0560.0423.399.8
6.06-214.7363.40.03814.4889126480.0290.0530.03824.399.7

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Processing

Software
NameVersionClassification
SCALA3.3.16data scaling
BUSTER2.11.7 (19-MAR-2020)refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
BUSTERphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 2SHP

2shp


Resolution: 1.917→107.37 Å / Cor.coef. Fo:Fc: 0.941 / Cor.coef. Fo:Fc free: 0.928 / SU R Cruickshank DPI: 0.146 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.15 / SU Rfree Blow DPI: 0.133 / SU Rfree Cruickshank DPI: 0.132
RfactorNum. reflection% reflectionSelection details
Rfree0.214 4106 5.01 %RANDOM
Rwork0.181 ---
obs0.1827 81963 99.9 %-
Displacement parametersBiso max: 103.23 Å2 / Biso mean: 29.49 Å2 / Biso min: 11.86 Å2
Baniso -1Baniso -2Baniso -3
1--6.1974 Å20 Å21.0235 Å2
2--3.0137 Å20 Å2
3---3.1836 Å2
Refine analyzeLuzzati coordinate error obs: 0.23 Å
Refinement stepCycle: final / Resolution: 1.917→107.37 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7673 0 83 738 8494
Biso mean--42.08 38.19 -
Num. residues----946
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d2849SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes1346HARMONIC5
X-RAY DIFFRACTIONt_it7946HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion994SEMIHARMONIC5
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_contact7147SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d7946HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg10728HARMONIC20.93
X-RAY DIFFRACTIONt_omega_torsion3.4
X-RAY DIFFRACTIONt_other_torsion17.78
LS refinement shellResolution: 1.92→1.93 Å / Rfactor Rfree error: 0 / Total num. of bins used: 51
RfactorNum. reflection% reflection
Rfree0.2374 84 5.12 %
Rwork0.2069 1556 -
all0.2084 1640 -
obs--99.82 %

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