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

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Basic information

Entry
Database: PDB / ID: 6bmy
TitleNon-receptor Protein Tyrosine Phosphatase SHP2 in Complex with Allosteric Inhibitors SHP099 and SHP844
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 / 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-5OD / Chem-DYV / PHOSPHATE ION / Tyrosine-protein phosphatase non-receptor type 11
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.09 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 / software
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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)123,08712
Polymers120,6702
Non-polymers2,41710
Water8,575476
1
A: Tyrosine-protein phosphatase non-receptor type 11
hetero molecules


Theoretical massNumber of molelcules
Total (without water)61,3564
Polymers60,3351
Non-polymers1,0213
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)61,7308
Polymers60,3351
Non-polymers1,3957
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)46.050, 213.710, 55.980
Angle α, β, γ (deg.)90.00, 96.71, 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, 486 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-DYV / 1-(3-chloro-4-{[1-(2-hydroxy-3-methoxyphenyl)-5-oxo[1,2,4]triazolo[4,3-a]quinazolin-4(5H)-yl]methyl}benzene-1-carbonyl)-L-proline


Mass: 573.984 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C29H24ClN5O6 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-PO4 / PHOSPHATE ION


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


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 476 / 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: 45.75 %
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: 2.085→213.709 Å / Num. obs: 59793 / % possible obs: 94 % / Redundancy: 3.4 % / Biso Wilson estimate: 36.03 Å2 / CC1/2: 0.997 / Rmerge(I) obs: 0.079 / Net I/σ(I): 10.4
Reflection shellResolution: 2.085→2.092 Å / Redundancy: 3.3 % / Rmerge(I) obs: 0.568 / Mean I/σ(I) obs: 3.3 / Num. unique obs: 453 / CC1/2: 0.804 / % possible all: 67.2

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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: 2.09→106.85 Å / Cor.coef. Fo:Fc: 0.934 / Cor.coef. Fo:Fc free: 0.898 / SU R Cruickshank DPI: 0.218 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.216 / SU Rfree Blow DPI: 0.18 / SU Rfree Cruickshank DPI: 0.182
RfactorNum. reflection% reflectionSelection details
Rfree0.228 2926 4.92 %RANDOM
Rwork0.18 ---
obs0.182 59508 94.2 %-
Displacement parametersBiso mean: 41.52 Å2
Baniso -1Baniso -2Baniso -3
1--13.2954 Å20 Å20.388 Å2
2--7.4781 Å20 Å2
3---5.8173 Å2
Refine analyzeLuzzati coordinate error obs: 0.25 Å
Refinement stepCycle: 1 / Resolution: 2.09→106.85 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7731 0 160 476 8367
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.018082HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.0610919HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d2858SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes212HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1151HARMONIC5
X-RAY DIFFRACTIONt_it8082HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.28
X-RAY DIFFRACTIONt_other_torsion18.8
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion998SEMIHARMONIC5
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_contact9395SEMIHARMONIC4
LS refinement shellResolution: 2.09→2.14 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2664 216 4.67 %
Rwork0.2071 4408 -
all0.2098 4624 -
obs--99.74 %

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