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

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Basic information

Entry
Database: PDB / ID: 6bmr
TitleNon-receptor Protein Tyrosine Phosphatase SHP2 in Complex with Allosteric Inhibitor 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


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 / Co-inhibition by BTLA / Netrin mediated repulsion signals ...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 / Co-inhibition by BTLA / Netrin mediated repulsion signals / negative regulation of neutrophil activation / cerebellar cortex formation / positive regulation of hormone secretion / regulation of protein export from nucleus / Interleukin-37 signaling / positive regulation of lipopolysaccharide-mediated signaling pathway / positive regulation of ossification / Signaling by Leptin / MET activates PTPN11 / hormone metabolic process / Regulation of RUNX1 Expression and Activity / negative regulation of chondrocyte differentiation / Signal regulatory protein family interactions / face morphogenesis / ERBB signaling pathway / platelet formation / triglyceride metabolic process / megakaryocyte development / negative regulation of type I interferon production / organ growth / Interleukin-20 family signaling / Interleukin-6 signaling / PI-3K cascade:FGFR3 / Co-inhibition by CTLA4 / Platelet sensitization by LDL / STAT5 activation downstream of FLT3 ITD mutants / peptide hormone receptor binding / PI-3K cascade:FGFR2 / PI-3K cascade:FGFR4 / PI-3K cascade:FGFR1 / MAPK3 (ERK1) activation / Prolactin receptor signaling / neurotrophin TRK receptor signaling pathway / regulation of cell adhesion mediated by integrin / regulation of type I interferon-mediated signaling pathway / MAPK1 (ERK2) activation / platelet-derived growth factor receptor signaling pathway / PECAM1 interactions / Bergmann glial cell differentiation / inner ear development / peptidyl-tyrosine dephosphorylation / non-membrane spanning protein tyrosine phosphatase activity / positive regulation of intracellular signal transduction / phosphoprotein phosphatase activity / Regulation of IFNA/IFNB signaling / RET signaling / Interleukin-3, Interleukin-5 and GM-CSF signaling / PI3K Cascade / Co-inhibition by PD-1 / fibroblast growth factor receptor signaling pathway / positive regulation of insulin receptor signaling pathway / GAB1 signalosome / ephrin receptor signaling pathway / regulation of protein-containing complex assembly / Regulation of IFNG signaling / Activated NTRK2 signals through FRS2 and FRS3 / GPVI-mediated activation cascade / FRS-mediated FGFR3 signaling / Signaling by CSF3 (G-CSF) / cell adhesion molecule binding / negative regulation of T cell proliferation / Signaling by FLT3 ITD and TKD mutants / T cell costimulation / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / FRS-mediated FGFR1 signaling / hormone-mediated signaling pathway / Tie2 Signaling / phosphotyrosine residue binding / protein-tyrosine-phosphatase / FLT3 Signaling / homeostasis of number of cells within a tissue / Downstream signal transduction / positive regulation of mitotic cell cycle / axonogenesis / protein tyrosine phosphatase activity / positive regulation of interferon-beta production / protein tyrosine kinase binding / cellular response to epidermal growth factor stimulus / DNA damage checkpoint signaling / Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE) / integrin-mediated signaling pathway / positive regulation of D-glucose import / insulin receptor binding / Negative regulation of FGFR3 signaling / Negative regulation of FGFR2 signaling / Negative regulation of FGFR4 signaling / Negative regulation of FGFR1 signaling / cellular response to mechanical stimulus / Spry regulation of FGF signaling
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-DZV / PHOSPHATE ION / Tyrosine-protein phosphatase non-receptor type 11
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.205 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

Downloads & links

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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)122,38813
Polymers120,6702
Non-polymers1,71811
Water13,241735
1
A: Tyrosine-protein phosphatase non-receptor type 11
hetero molecules


Theoretical massNumber of molelcules
Total (without water)61,2437
Polymers60,3351
Non-polymers9086
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)61,1456
Polymers60,3351
Non-polymers8105
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)46.230, 214.660, 56.030
Angle α, β, γ (deg.)90.00, 96.96, 90.00
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
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-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
#3: Chemical
ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: PO4
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 735 / 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: 2.29 Å3/Da / Density % sol: 46.22 %
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: Oct 3, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.205→107.33 Å / Num. obs: 54204 / % possible obs: 99.8 % / Redundancy: 3.4 % / Biso Wilson estimate: 37.03 Å2 / CC1/2: 0.991 / Rmerge(I) obs: 0.149 / Net I/σ(I): 8.2
Reflection shellResolution: 2.205→2.212 Å / Redundancy: 3.5 % / Rmerge(I) obs: 0.916 / Mean I/σ(I) obs: 2.1 / Num. unique obs: 534 / CC1/2: 0.633 / % possible all: 99.8

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
XDSdata reduction
autoPROCdata scaling
BUSTERphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 5EHR

5ehr


Resolution: 2.205→107 Å / Cor.coef. Fo:Fc: 0.943 / Cor.coef. Fo:Fc free: 0.913 / SU R Cruickshank DPI: 0.247 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.259 / SU Rfree Blow DPI: 0.199 / SU Rfree Cruickshank DPI: 0.198
RfactorNum. reflection% reflectionSelection details
Rfree0.224 2760 5.1 %RANDOM
Rwork0.167 ---
obs0.17 54144 99 %-
Displacement parametersBiso mean: 40.45 Å2
Baniso -1Baniso -2Baniso -3
1--9.3801 Å20 Å21.9026 Å2
2--6.3668 Å20 Å2
3---3.0133 Å2
Refine analyzeLuzzati coordinate error obs: 0.25 Å
Refinement stepCycle: 1 / Resolution: 2.205→107 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7852 0 108 735 8695
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.018132HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.0910978HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d2886SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes220HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1154HARMONIC5
X-RAY DIFFRACTIONt_it8132HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.17
X-RAY DIFFRACTIONt_other_torsion20.05
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1010SEMIHARMONIC5
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_contact9573SEMIHARMONIC4
LS refinement shellResolution: 2.205→2.26 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2552 185 5.09 %
Rwork0.2094 3450 -
all0.2117 3635 -
obs--91.31 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.34350.2986-0.14461.0262-0.07580.33990.00140.02290.0196-0.06350.022-0.0849-0.0429-0.0313-0.0234-0.0004-0.003-0.0282-0.07830.0062-0.076318.444733.300914.7073
20.23990.31220.06721.1270.08030.3138-0.05020.03260.0056-0.12670.05810.10380.02680.0427-0.0080.0191-0.0015-0.0446-0.0792-0.0019-0.089222.1555-16.322237.8297
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|* }
2X-RAY DIFFRACTION2{ B|* }

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