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- PDB-9blg: Crystal structure of non-receptor protein tyrosine phosphatase SH... -

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Basic information

Entry
Database: PDB / ID: 9blg
TitleCrystal structure of non-receptor protein tyrosine phosphatase SHP2 in complex with PF-07284892
ComponentsTyrosine-protein phosphatase non-receptor type 11
KeywordsHYDROLASE/INHIBITOR / PHOSPHATASE / INHIBITOR / SHP2 / 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
: / Tyrosine-protein phosphatase non-receptor type 11
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.06 Å
AuthorsBester, S.M. / Wu, W.-I. / Mou, T.-C.
Funding support United States, 1items
OrganizationGrant numberCountry
Other private United States
CitationJournal: Cancer Discov / Year: 2023
Title: SHP2 Inhibition Sensitizes Diverse Oncogene-Addicted Solid Tumors to Re-treatment with Targeted Therapy.
Authors: Drilon, A. / Sharma, M.R. / Johnson, M.L. / Yap, T.A. / Gadgeel, S. / Nepert, D. / Feng, G. / Reddy, M.B. / Harney, A.S. / Elsayed, M. / Cook, A.W. / Wong, C.E. / Hinklin, R.J. / Jiang, Y. / ...Authors: Drilon, A. / Sharma, M.R. / Johnson, M.L. / Yap, T.A. / Gadgeel, S. / Nepert, D. / Feng, G. / Reddy, M.B. / Harney, A.S. / Elsayed, M. / Cook, A.W. / Wong, C.E. / Hinklin, R.J. / Jiang, Y. / Brown, E.N. / Neitzel, N.A. / Laird, E.R. / Wu, W.I. / Singh, A. / Wei, P. / Ching, K.A. / Gaudino, J.J. / Lee, P.A. / Hartley, D.P. / Rothenberg, S.M.
History
DepositionApr 30, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 29, 2024Provider: repository / Type: Initial release

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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)125,0604
Polymers124,1802
Non-polymers8802
Water8,647480
1
A: Tyrosine-protein phosphatase non-receptor type 11
hetero molecules


  • defined by author
  • 62.5 kDa, 1 polymers
Theoretical massNumber of molelcules
Total (without water)62,5302
Polymers62,0901
Non-polymers4401
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Tyrosine-protein phosphatase non-receptor type 11
hetero molecules


  • defined by author
  • 62.5 kDa, 1 polymers
Theoretical massNumber of molelcules
Total (without water)62,5302
Polymers62,0901
Non-polymers4401
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)45.270, 214.270, 55.810
Angle α, β, γ (deg.)90.00, 96.06, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Tyrosine-protein phosphatase non-receptor type 11


Mass: 62089.973 Da / Num. of mol.: 2 / Fragment: residues 1-525
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: PTPN11 / Production host: Escherichia coli (E. coli) / References: UniProt: Q06124
#2: Chemical ChemComp-A1AQ1 / (1S)-1'-{6-[(2-amino-3-chloropyridin-4-yl)sulfanyl]-1,2,4-triazin-3-yl}-1,3-dihydrospiro[indene-2,4'-piperidin]-1-amine / PF-07284892


Mass: 439.964 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H22ClN7S / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 480 / 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: 2.17 Å3/Da / Density % sol: 43.25 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 9.2
Details: 9%PEG3350, 0.1M Bicine, pH9.2, 30mM Ammonium Acetate, 5% Tacsimate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.54 Å
DetectorType: DECTRIS PILATUS3 R 1M / Detector: PIXEL / Date: Mar 14, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2.06→28.27 Å / Num. obs: 61141 / % possible obs: 94.3 % / Redundancy: 6.9 % / Biso Wilson estimate: 22.65 Å2 / CC1/2: 0.998 / Rpim(I) all: 0.029 / Rrim(I) all: 0.077 / Net I/σ(I): 17.6
Reflection shellResolution: 2.06→2.14 Å / Mean I/σ(I) obs: 7.2 / Num. unique obs: 8644 / CC1/2: 0.973 / Rpim(I) all: 0.097 / Rrim(I) all: 0.244

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Processing

Software
NameVersionClassification
PHENIX1.19.1_4122refinement
iMOSFLMdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.06→28.27 Å / SU ML: 0.23 / Cross valid method: FREE R-VALUE / σ(F): 0.31 / Phase error: 23.04 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2381 3053 5 %
Rwork0.1876 --
obs0.1901 61091 94.32 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.06→28.27 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8089 0 60 480 8629
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0028357
X-RAY DIFFRACTIONf_angle_d0.48911288
X-RAY DIFFRACTIONf_dihedral_angle_d4.8181112
X-RAY DIFFRACTIONf_chiral_restr0.0411202
X-RAY DIFFRACTIONf_plane_restr0.0031463
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.06-2.090.26221520.22662345X-RAY DIFFRACTION87
2.09-2.130.2411390.2152608X-RAY DIFFRACTION93
2.13-2.160.26271400.21832657X-RAY DIFFRACTION94
2.16-2.20.25711410.21012566X-RAY DIFFRACTION94
2.2-2.250.25861670.21422666X-RAY DIFFRACTION94
2.25-2.290.26851370.20692591X-RAY DIFFRACTION94
2.29-2.340.25931310.20862688X-RAY DIFFRACTION94
2.34-2.40.25381540.19922600X-RAY DIFFRACTION94
2.4-2.460.2751240.20462633X-RAY DIFFRACTION94
2.46-2.520.27711480.20992700X-RAY DIFFRACTION94
2.52-2.60.26671210.19492605X-RAY DIFFRACTION94
2.6-2.680.25511010.21322672X-RAY DIFFRACTION94
2.68-2.780.27241410.20482563X-RAY DIFFRACTION92
2.78-2.890.25431340.20682567X-RAY DIFFRACTION93
2.89-3.020.27781550.21422718X-RAY DIFFRACTION96
3.02-3.180.23091360.19972683X-RAY DIFFRACTION97
3.18-3.380.23551460.18562707X-RAY DIFFRACTION97
3.38-3.640.24251390.17672721X-RAY DIFFRACTION97
3.64-40.2081580.16292725X-RAY DIFFRACTION97
4-4.580.20371280.14792705X-RAY DIFFRACTION97
4.58-5.760.21921260.16082679X-RAY DIFFRACTION94
5.76-28.270.18121350.17292639X-RAY DIFFRACTION93

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