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

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Basic information

Entry
Database: PDB / ID: 7rct
TitleNon-receptor Protein Tyrosine Phosphatase SHP2 in Complex with Allosteric Inhibitor RMC-4550
ComponentsTyrosine-protein phosphatase non-receptor type 11
KeywordsSIGNALING PROTEIN / SHP2 RMC-4550 phosphatase
Function / homology
Function and homology information


atrioventricular canal development / genitalia development / STAT5 Activation / Co-inhibition by BTLA / Netrin mediated repulsion signals / negative regulation of neutrophil activation / negative regulation of chondrocyte differentiation / positive regulation of lipopolysaccharide-mediated signaling pathway / face morphogenesis / Interleukin-37 signaling ...atrioventricular canal development / genitalia development / STAT5 Activation / Co-inhibition by BTLA / Netrin mediated repulsion signals / negative regulation of neutrophil activation / negative regulation of chondrocyte differentiation / positive regulation of lipopolysaccharide-mediated signaling pathway / face morphogenesis / Interleukin-37 signaling / positive regulation of ossification / Signaling by Leptin / negative regulation of cell adhesion mediated by integrin / MET activates PTPN11 / Regulation of RUNX1 Expression and Activity / Signal regulatory protein family interactions / ERBB signaling pathway / Interleukin-20 family signaling / Interleukin-6 signaling / Co-inhibition by CTLA4 / PI-3K cascade:FGFR3 / STAT5 activation downstream of FLT3 ITD mutants / Platelet sensitization by LDL / negative regulation of T cell activation / inner ear development / fibroblast growth factor receptor signaling pathway / PI-3K cascade:FGFR2 / PI-3K cascade:FGFR4 / peptide hormone receptor binding / negative regulation of type I interferon production / MAPK3 (ERK1) activation / PI-3K cascade:FGFR1 / regulation of type I interferon-mediated signaling pathway / MAPK1 (ERK2) activation / Prolactin receptor signaling / PECAM1 interactions / non-membrane spanning protein tyrosine phosphatase activity / peptidyl-tyrosine dephosphorylation / Regulation of IFNA/IFNB signaling / positive regulation of intracellular signal transduction / RET signaling / Interleukin-3, Interleukin-5 and GM-CSF signaling / Co-inhibition by PD-1 / PI3K Cascade / ephrin receptor signaling pathway / positive regulation of insulin receptor signaling pathway / regulation of protein-containing complex assembly / negative regulation of T cell receptor signaling pathway / negative regulation of T cell proliferation / Regulation of IFNG signaling / GAB1 signalosome / T cell costimulation / Activated NTRK2 signals through FRS2 and FRS3 / GPVI-mediated activation cascade / Signaling by CSF3 (G-CSF) / FRS-mediated FGFR3 signaling / Signaling by FLT3 ITD and TKD mutants / phosphotyrosine residue binding / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / phosphoprotein phosphatase activity / protein-tyrosine-phosphatase / FRS-mediated FGFR1 signaling / Tie2 Signaling / positive regulation of D-glucose import across plasma membrane / FLT3 Signaling / protein tyrosine phosphatase activity / cell adhesion molecule binding / positive regulation of interferon-beta production / Downstream signal transduction / cellular response to epidermal growth factor stimulus / protein tyrosine kinase binding / insulin receptor binding / Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE) / brain development / Negative regulation of FGFR3 signaling / cellular response to mechanical stimulus / Negative regulation of FGFR2 signaling / Negative regulation of FGFR4 signaling / Negative regulation of FGFR1 signaling / Signaling by SCF-KIT / Spry regulation of FGF signaling / receptor tyrosine kinase binding / vasodilation / epidermal growth factor receptor signaling pathway / cytokine-mediated signaling pathway / Constitutive Signaling by Aberrant PI3K in Cancer / heart development / Signaling by CSF1 (M-CSF) in myeloid cells / Interferon alpha/beta signaling / positive regulation of tumor necrosis factor production / PIP3 activates AKT signaling / PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling / signaling receptor complex adaptor activity / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / molecular adaptor activity / positive regulation of ERK1 and ERK2 cascade / cadherin binding / focal adhesion / nucleolus
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-4Q4 / Tyrosine-protein phosphatase non-receptor type 11
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsSeegar, T.C.M.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)R35 CA220340 United States
CitationJournal: Biochemistry / Year: 2021
Title: Targeted Degradation of the Oncogenic Phosphatase SHP2.
Authors: Vemulapalli, V. / Donovan, K.A. / Seegar, T.C.M. / Rogers, J.M. / Bae, M. / Lumpkin, R.J. / Cao, R. / Henke, M.T. / Ray, S.S. / Fischer, E.S. / Cuny, G.D. / Blacklow, S.C.
History
DepositionJul 8, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 1, 2021Provider: repository / Type: Initial release
Revision 1.1Sep 15, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.3Oct 9, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
B: Tyrosine-protein phosphatase non-receptor type 11
A: Tyrosine-protein phosphatase non-receptor type 11
hetero molecules


Theoretical massNumber of molelcules
Total (without water)121,4426
Polymers120,4962
Non-polymers9464
Water12,484693
1
B: Tyrosine-protein phosphatase non-receptor type 11
hetero molecules


Theoretical massNumber of molelcules
Total (without water)60,7564
Polymers60,2481
Non-polymers5083
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
A: Tyrosine-protein phosphatase non-receptor type 11
hetero molecules


Theoretical massNumber of molelcules
Total (without water)60,6852
Polymers60,2481
Non-polymers4371
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)45.790, 213.780, 55.850
Angle α, β, γ (deg.)90.000, 96.830, 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: 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-4Q4 / {3-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-6-(2,3-dichlorophenyl)-5-methylpyrazin-2-yl}methanol


Mass: 437.363 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H26Cl2N4O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 693 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 2.38 Å3/Da / Density % sol: 48.38 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop
Details: 0.1 M Sodium Chloride 0.1 M BIS-TRIS propane pH 8.5 11% PEG 1500

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Data collection

DiffractionMean temperature: 93 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.979 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jun 12, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 1.8→44.47 Å / Num. obs: 96389 / % possible obs: 98.29 % / Redundancy: 3 % / Biso Wilson estimate: 30.73 Å2 / CC1/2: 0.999 / Net I/σ(I): 10.87
Reflection shellResolution: 1.8→1.865 Å / Num. unique obs: 9595 / CC1/2: 0.422

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Processing

Software
NameVersionClassification
PHENIX1.19.1_4122+SVNrefinement
XDSdata scaling
PHENIXphasing
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5EHR

5ehr


Resolution: 1.8→44.47 Å / SU ML: 0.3056 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 28.4701
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2252 1997 2.07 %
Rwork0.1845 94344 -
obs0.1854 96341 98.3 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 41.06 Å2
Refinement stepCycle: LAST / Resolution: 1.8→44.47 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8010 0 60 693 8763
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00658291
X-RAY DIFFRACTIONf_angle_d0.778711208
X-RAY DIFFRACTIONf_chiral_restr0.05221203
X-RAY DIFFRACTIONf_plane_restr0.00651448
X-RAY DIFFRACTIONf_dihedral_angle_d12.62163132
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.8-1.850.41711410.40016638X-RAY DIFFRACTION96.82
1.85-1.90.34371440.34266805X-RAY DIFFRACTION99.68
1.9-1.950.35081440.29686808X-RAY DIFFRACTION99.5
1.95-2.010.33191450.27936789X-RAY DIFFRACTION99.27
2.01-2.090.31281430.2576789X-RAY DIFFRACTION98.82
2.09-2.170.26821430.21736713X-RAY DIFFRACTION98.05
2.17-2.270.25211390.19716618X-RAY DIFFRACTION96.83
2.27-2.390.2321440.1896804X-RAY DIFFRACTION99.54
2.39-2.540.24741460.19166876X-RAY DIFFRACTION99.52
2.54-2.730.24971430.19656751X-RAY DIFFRACTION99.14
2.73-3.010.24281410.18396724X-RAY DIFFRACTION98.45
3.01-3.440.22921410.16486632X-RAY DIFFRACTION96.34
3.44-4.340.1571430.14096756X-RAY DIFFRACTION98.21
4.34-44.470.18471400.1536641X-RAY DIFFRACTION95.99

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