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- PDB-6wu8: Structure of human SHP2 in complex with inhibitor IACS-13909 -

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Basic information

Entry
Database: PDB / ID: 6wu8
TitleStructure of human SHP2 in complex with inhibitor IACS-13909
ComponentsTyrosine-protein phosphatase non-receptor type 11
KeywordsHYDROLASE/HYDROLASE INHIBITOR / Phosphatase / Inhibitor / Complex / 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 / 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 ...Protein-tyrosine phosphatase, non-receptor type-6, -11 / 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
Similarity search - Domain/homology
Chem-U9Y / Tyrosine-protein phosphatase non-receptor type 11
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.4 Å
AuthorsLeonard, P.G. / Joseph, S. / Rodenberger, A.
CitationJournal: Cancer Res. / Year: 2020
Title: Allosteric SHP2 Inhibitor, IACS-13909, Overcomes EGFR-Dependent and EGFR-Independent Resistance Mechanisms toward Osimertinib.
Authors: Sun, Y. / Meyers, B.A. / Czako, B. / Leonard, P. / Mseeh, F. / Harris, A.L. / Wu, Q. / Johnson, S. / Parker, C.A. / Cross, J.B. / Di Francesco, M.E. / Bivona, B.J. / Bristow, C.A. / Burke, J. ...Authors: Sun, Y. / Meyers, B.A. / Czako, B. / Leonard, P. / Mseeh, F. / Harris, A.L. / Wu, Q. / Johnson, S. / Parker, C.A. / Cross, J.B. / Di Francesco, M.E. / Bivona, B.J. / Bristow, C.A. / Burke, J.P. / Carrillo, C.C. / Carroll, C.L. / Chang, Q. / Feng, N. / Gao, G. / Gera, S. / Giuliani, V. / Huang, J.K. / Jiang, Y. / Kang, Z. / Kovacs, J.J. / Liu, C.Y. / Lopez, A.M. / Ma, X. / Mandal, P.K. / McAfoos, T. / Miller, M.A. / Mullinax, R.A. / Peoples, M. / Ramamoorthy, V. / Seth, S. / Spencer, N.D. / Suzuki, E. / Williams, C.C. / Yu, S.S. / Zuniga, A.M. / Draetta, G.F. / Marszalek, J.R. / Heffernan, T.P. / Kohl, N.E. / Jones, P.
History
DepositionMay 4, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 17, 2021Provider: repository / Type: Initial release
Revision 1.1Oct 18, 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
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)123,7374
Polymers122,9832
Non-polymers7552
Water4,107228
1
A: Tyrosine-protein phosphatase non-receptor type 11
hetero molecules


Theoretical massNumber of molelcules
Total (without water)61,8692
Polymers61,4911
Non-polymers3771
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Tyrosine-protein phosphatase non-receptor type 11
hetero molecules


Theoretical massNumber of molelcules
Total (without water)61,8692
Polymers61,4911
Non-polymers3771
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)54.671, 83.203, 217.701
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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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: 61491.398 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-U9Y / 1-[3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-4-methylpiperidin-4-amine


Mass: 377.271 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C17H18Cl2N6 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 228 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.03 Å3/Da / Density % sol: 39.45 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8 / Details: 300 mM potassium formate, 14% w/v PEG3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 8.3.1 / Wavelength: 1.11583 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Jun 2, 2016
RadiationMonochromator: Water-cooled flat double Si(111) Khozu / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.11583 Å / Relative weight: 1
ReflectionResolution: 2.4→42.13 Å / Num. obs: 37950 / % possible obs: 95.3 % / Redundancy: 10.4 % / CC1/2: 0.992 / Rmerge(I) obs: 0.202 / Rpim(I) all: 0.064 / Rrim(I) all: 0.212 / Net I/σ(I): 8.1 / Num. measured all: 395923 / Scaling rejects: 118
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.4-2.4910.11.6223769537260.4050.5231.7091.890.6
8.98-42.1310.40.06891438750.9980.0220.0722099.2

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation6.06 Å42.13 Å
Translation6.06 Å42.13 Å

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Processing

Software
NameVersionClassification
PHENIXv1.17.1-3660refinement
MOSFLM7.1.0data reduction
Aimless0.3.11data scaling
PHASER2.6.0phasing
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 2SHP

2shp


Resolution: 2.4→42.129 Å / SU ML: 0.33 / Cross valid method: THROUGHOUT / σ(F): 1.36 / Phase error: 30.72
RfactorNum. reflection% reflection
Rfree0.2704 1896 5.01 %
Rwork0.2095 --
obs0.2126 37809 94.96 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 94.73 Å2 / Biso mean: 41.3443 Å2 / Biso min: 13.16 Å2
Refinement stepCycle: final / Resolution: 2.4→42.129 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8032 0 50 228 8310
Biso mean--35.78 37.7 -
Num. residues----991
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2.4-2.460.32451150.2772239790
2.46-2.52650.33851110.2781239690
2.5265-2.60090.34821280.2724241290
2.6009-2.68480.38541240.2582238189
2.6848-2.78070.3121360.265236890
2.7807-2.89210.33221520.2553241391
2.8921-3.02360.31091130.2601251893
3.0236-3.1830.34111280.2489258797
3.183-3.38240.33541240.2194266699
3.3824-3.64340.26131550.20042705100
3.6434-4.00980.25981460.18482691100
4.0098-4.58940.22831480.15672739100
4.5894-5.77980.21711610.17062730100
5.7798-42.1290.21251550.19472910100

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