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- PDB-6bmu: Non-receptor Protein Tyrosine Phosphatase SHP2 in Complex with Al... -

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Basic information

Entry
Database: PDB / ID: 6bmu
TitleNon-receptor Protein Tyrosine Phosphatase SHP2 in Complex with Allosteric Inhibitors SHP099 and SHP244
ComponentsTyrosine-protein phosphatase non-receptor type 11
KeywordsHYDROLASE/HYDROLASE INHIBITOR / SHP2 / PTPN11 / protein tyrosine phosphatase / phosphatase / allosteric inhibitor / HYDROLASE-HYDROLASE INHIBITOR complex
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-5OD / Chem-DZV / 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
AuthorsStams, T. / Fodor, M.
CitationJournal: ACS Chem. Biol. / Year: 2018
Title: Dual Allosteric Inhibition of SHP2 Phosphatase.
Authors: Fodor, M. / Price, E. / Wang, P. / Lu, H. / Argintaru, A. / Chen, Z. / Glick, M. / Hao, H.X. / Kato, M. / Koenig, R. / LaRochelle, J.R. / Liu, G. / McNeill, E. / Majumdar, D. / Nishiguchi, G. ...Authors: Fodor, M. / Price, E. / Wang, P. / Lu, H. / Argintaru, A. / Chen, Z. / Glick, M. / Hao, H.X. / Kato, M. / Koenig, R. / LaRochelle, J.R. / Liu, G. / McNeill, E. / Majumdar, D. / Nishiguchi, G.A. / Perez, L.B. / Paris, G. / Quinn, C.M. / Ramsey, T. / Sendzik, M. / Shultz, M.D. / Williams, S.L. / Stams, T. / Blacklow, S.C. / Acker, M.G. / LaMarche, M.J.
History
DepositionNov 15, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 17, 2018Provider: repository / Type: Initial release
Revision 1.1Mar 28, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Oct 4, 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 / refine_hist / software
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _refine_hist.d_res_low / _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)122,70711
Polymers120,6702
Non-polymers2,0369
Water8,773487
1
A: Tyrosine-protein phosphatase non-receptor type 11
hetero molecules


Theoretical massNumber of molelcules
Total (without water)61,3075
Polymers60,3351
Non-polymers9724
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)61,3996
Polymers60,3351
Non-polymers1,0645
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)46.130, 213.450, 55.940
Angle α, β, γ (deg.)90.00, 96.75, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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Protein , 1 types, 2 molecules AB

#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

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Non-polymers , 5 types, 496 molecules

#2: Chemical ChemComp-5OD / 6-(4-azanyl-4-methyl-piperidin-1-yl)-3-[2,3-bis(chloranyl)phenyl]pyrazin-2-amine / SHP099


Mass: 352.262 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C16H19Cl2N5 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-DZV / 4-[(2-chlorophenyl)methyl]-1-(2-hydroxy-3-methoxyphenyl)[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one


Mass: 432.859 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C23H17ClN4O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: PO4
#5: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C3H8O3
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 487 / 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: 2.27 Å3/Da / Density % sol: 45.73 %
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: Jun 14, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.116→213.45 Å / Num. obs: 59399 / % possible obs: 97.4 % / Redundancy: 5.1 % / Biso Wilson estimate: 37.84 Å2 / CC1/2: 0.996 / Rmerge(I) obs: 0.108 / Net I/σ(I): 9.9
Reflection shellResolution: 2.116→2.123 Å / Redundancy: 5 % / Rmerge(I) obs: 0.76 / Mean I/σ(I) obs: 1.9 / Num. unique obs: 614 / CC1/2: 0.737 / % possible all: 97.9

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
XDSdata reduction
autoPROCdata scaling
BUSTERphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 6BMR

6bmr


Resolution: 2.12→55.55 Å / Cor.coef. Fo:Fc: 0.935 / Cor.coef. Fo:Fc free: 0.916 / SU R Cruickshank DPI: 0.221 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.22 / SU Rfree Blow DPI: 0.179 / SU Rfree Cruickshank DPI: 0.181
RfactorNum. reflection% reflectionSelection details
Rfree0.225 2895 4.91 %RANDOM
Rwork0.181 ---
obs0.183 58969 97.3 %-
Displacement parametersBiso mean: 42.56 Å2
Baniso -1Baniso -2Baniso -3
1--12.2486 Å20 Å22.5606 Å2
2--6.3068 Å20 Å2
3---5.9418 Å2
Refine analyzeLuzzati coordinate error obs: 0.25 Å
Refinement stepCycle: 1 / Resolution: 2.12→55.55 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7731 0 136 487 8354
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.018048HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.0610864HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d2840SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes212HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1142HARMONIC5
X-RAY DIFFRACTIONt_it8048HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.21
X-RAY DIFFRACTIONt_other_torsion18.19
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion995SEMIHARMONIC5
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_contact9346SEMIHARMONIC4
LS refinement shellResolution: 2.12→2.17 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2245 192 4.28 %
Rwork0.2058 4293 -
all0.2066 4485 -
obs--99.96 %

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