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- PDB-5ehp: Non-receptor Protein Tyrosine Phosphatase SHP2 in Complex with Al... -

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Basic information

Entry
Database: PDB / ID: 5ehp
TitleNon-receptor Protein Tyrosine Phosphatase SHP2 in Complex with Allosteric Inhibitor SHP836
ComponentsTyrosine-protein phosphatase non-receptor type 11
KeywordsHydrolase/Hydrolase Inhibitor / Phosphatase PTP Inhibitor PTPN11 Allosteric / 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 / regulation of protein export from nucleus / positive regulation of ossification / hormone metabolic process / Interleukin-37 signaling / Signaling by Leptin / MET activates PTPN11 / negative regulation of chondrocyte differentiation / Regulation of RUNX1 Expression and Activity / face morphogenesis / Costimulation by the CD28 family / ERBB signaling pathway / Signal regulatory protein family interactions / platelet formation / megakaryocyte development / triglyceride metabolic process / organ growth / negative regulation of type I interferon production / peptide hormone receptor binding / CTLA4 inhibitory signaling / Platelet sensitization by LDL / Interleukin-20 family signaling / PI-3K cascade:FGFR3 / Interleukin-6 signaling / PI-3K cascade:FGFR2 / STAT5 activation downstream of FLT3 ITD mutants / PI-3K cascade:FGFR4 / PI-3K cascade:FGFR1 / Prolactin receptor signaling / MAPK3 (ERK1) activation / regulation of cell adhesion mediated by integrin / PECAM1 interactions / regulation of type I interferon-mediated signaling pathway / MAPK1 (ERK2) activation / 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 / RET signaling / peptidyl-tyrosine dephosphorylation / Interleukin-3, Interleukin-5 and GM-CSF signaling / Regulation of IFNA/IFNB signaling / PI3K Cascade / PD-1 signaling / ephrin receptor signaling pathway / regulation of protein-containing complex assembly / 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 / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / GPVI-mediated activation cascade / homeostasis of number of cells within a tissue / Tie2 Signaling / FRS-mediated FGFR1 signaling / cell adhesion molecule binding / T cell costimulation / cellular response to epidermal growth factor stimulus / FLT3 Signaling / protein dephosphorylation / positive regulation of interferon-beta production / hormone-mediated signaling pathway / phosphotyrosine residue binding / Downstream signal transduction / positive regulation of mitotic cell cycle / protein-tyrosine-phosphatase / axonogenesis / protein tyrosine kinase binding / 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 FGFR3 signaling / Negative regulation of FGFR2 signaling / insulin receptor binding / Negative regulation of FGFR4 signaling / Negative regulation of FGFR1 signaling / Spry regulation of FGF signaling / epidermal growth factor receptor signaling pathway / Signaling by SCF-KIT
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-5OA / PHOSPHATE ION / Tyrosine-protein phosphatase non-receptor type 11
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.85 Å
AuthorsStams, T. / Fodor, M.
CitationJournal: J.Med.Chem. / Year: 2016
Title: Allosteric Inhibition of SHP2: Identification of a Potent, Selective, and Orally Efficacious Phosphatase Inhibitor.
Authors: Garcia Fortanet, J. / Chen, C.H. / Chen, Y.N. / Chen, Z. / Deng, Z. / Firestone, B. / Fekkes, P. / Fodor, M. / Fortin, P.D. / Fridrich, C. / Grunenfelder, D. / Ho, S. / Kang, Z.B. / Karki, R. ...Authors: Garcia Fortanet, J. / Chen, C.H. / Chen, Y.N. / Chen, Z. / Deng, Z. / Firestone, B. / Fekkes, P. / Fodor, M. / Fortin, P.D. / Fridrich, C. / Grunenfelder, D. / Ho, S. / Kang, Z.B. / Karki, R. / Kato, M. / Keen, N. / LaBonte, L.R. / Larrow, J. / Lenoir, F. / Liu, G. / Liu, S. / Lombardo, F. / Majumdar, D. / Meyer, M.J. / Palermo, M. / Perez, L. / Pu, M. / Ramsey, T. / Sellers, W.R. / Shultz, M.D. / Stams, T. / Towler, C. / Wang, P. / Williams, S.L. / Zhang, J.H. / LaMarche, M.J.
History
DepositionOct 28, 2015Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 6, 2016Provider: repository / Type: Initial release
Revision 1.1Sep 21, 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
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

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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)122,13412
Polymers120,6702
Non-polymers1,46410
Water11,764653
1
A: Tyrosine-protein phosphatase non-receptor type 11
hetero molecules


Theoretical massNumber of molelcules
Total (without water)61,1627
Polymers60,3351
Non-polymers8276
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)60,9725
Polymers60,3351
Non-polymers6374
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)46.310, 213.730, 55.980
Angle α, β, γ (deg.)90.000, 96.820, 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: 60335.035 Da / Num. of mol.: 2 / Fragment: UNP residues 1-525
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-5OA / 5-[2,3-bis(chloranyl)phenyl]-2-[(3~{R},5~{S})-3,5-dimethylpiperazin-1-yl]pyrimidin-4-amine / SHP836


Mass: 352.262 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C16H19Cl2N5
#3: Chemical
ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: PO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 653 / 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: 46.04 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / Details: 17% PEG 3350, 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: Feb 22, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.85→200 Å / Num. obs: 87497 / % possible obs: 95.9 % / Redundancy: 3.2 % / Rmerge(I) obs: 0.044 / Net I/σ(I): 15.9
Reflection shellResolution: 1.85→1.95 Å / Redundancy: 2.4 % / Rmerge(I) obs: 0.362 / Mean I/σ(I) obs: 2.1 / % possible all: 76.4

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Processing

Software
NameVersionClassification
XSCALEdata scaling
BUSTERBUSTER 2.11.5refinement
PDB_EXTRACT3.15data extraction
XDSdata reduction
BUSTERphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 2SHP

2shp


Resolution: 1.85→27.09 Å / Cor.coef. Fo:Fc: 0.9525 / Cor.coef. Fo:Fc free: 0.9375 / SU R Cruickshank DPI: 0.132 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.132 / SU Rfree Blow DPI: 0.122 / SU Rfree Cruickshank DPI: 0.122
RfactorNum. reflection% reflectionSelection details
Rfree0.2084 4388 5.02 %RANDOM
Rwork0.1745 ---
obs0.1762 87407 95.5 %-
Displacement parametersBiso max: 111.88 Å2 / Biso mean: 34.24 Å2 / Biso min: 12.78 Å2
Baniso -1Baniso -2Baniso -3
1--4.8841 Å20 Å21.8716 Å2
2--2.0054 Å20 Å2
3---2.8787 Å2
Refine analyzeLuzzati coordinate error obs: 0.195 Å
Refinement stepCycle: final / Resolution: 1.85→27.09 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7825 0 86 654 8565
Biso mean--49.56 39.27 -
Num. residues----965
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d2891SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes219HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1155HARMONIC5
X-RAY DIFFRACTIONt_it8104HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion1015SEMIHARMONIC5
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_contact9607SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d8104HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg10940HARMONIC21
X-RAY DIFFRACTIONt_omega_torsion3.32
X-RAY DIFFRACTIONt_other_torsion18.13
LS refinement shellResolution: 1.85→1.9 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2643 257 5.65 %
Rwork0.2225 4290 -
all0.2248 4547 -
obs--95.5 %

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