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- PDB-8gww: Small-molecule Allosteric Regulation Mechanism of SHP2 -

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Basic information

Entry
Database: PDB / ID: 8gww
TitleSmall-molecule Allosteric Regulation Mechanism of SHP2
ComponentsTyrosine-protein phosphatase non-receptor type 11
KeywordsONCOPROTEIN/INHIBITOR / phosphatase / ONCOPROTEIN-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 / Netrin mediated repulsion signals / positive regulation of hormone secretion ...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 / Netrin mediated repulsion signals / positive regulation of hormone secretion / cerebellar cortex formation / multicellular organismal reproductive process / regulation of protein export from nucleus / positive regulation of ossification / hormone metabolic process / Interleukin-37 signaling / negative regulation of chondrocyte differentiation / Signaling by Leptin / MET activates PTPN11 / Regulation of RUNX1 Expression and Activity / face morphogenesis / ERBB signaling pathway / Costimulation by the CD28 family / Signal regulatory protein family interactions / peptide hormone receptor binding / triglyceride metabolic process / platelet formation / negative regulation of type I interferon production / megakaryocyte development / organ growth / CTLA4 inhibitory signaling / Platelet sensitization by LDL / Interleukin-20 family signaling / PI-3K cascade:FGFR3 / Interleukin-6 signaling / STAT5 activation downstream of FLT3 ITD mutants / PI-3K cascade:FGFR2 / PI-3K cascade:FGFR4 / Prolactin receptor signaling / PI-3K cascade:FGFR1 / MAPK3 (ERK1) activation / phosphoprotein phosphatase activity / inner ear development / MAPK1 (ERK2) activation / PECAM1 interactions / Bergmann glial cell differentiation / regulation of cell adhesion mediated by integrin / neurotrophin TRK receptor signaling pathway / regulation of type I interferon-mediated signaling pathway / 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 / PI3K Cascade / Regulation of IFNA/IFNB signaling / PD-1 signaling / negative regulation of insulin secretion / 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 / Regulation of IFNG signaling / positive regulation of insulin receptor signaling pathway / homeostasis of number of cells within a tissue / FRS-mediated FGFR3 signaling / Signaling by CSF3 (G-CSF) / Signaling by FLT3 ITD and TKD mutants / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / cellular response to epidermal growth factor stimulus / FRS-mediated FGFR1 signaling / GPVI-mediated activation cascade / Tie2 Signaling / protein tyrosine kinase binding / T cell costimulation / FLT3 Signaling / positive regulation of interferon-beta production / hormone-mediated signaling pathway / cell adhesion molecule binding / phosphotyrosine residue binding / positive regulation of mitotic cell cycle / axonogenesis / Downstream signal transduction / protein dephosphorylation / Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE) / protein-tyrosine-phosphatase / DNA damage checkpoint signaling / protein tyrosine phosphatase activity / integrin-mediated signaling pathway / Negative regulation of FGFR3 signaling / Negative regulation of FGFR2 signaling / positive regulation of glucose import / Negative regulation of FGFR4 signaling / Negative regulation of FGFR1 signaling / brain development / Spry regulation of FGF signaling / multicellular organism growth / insulin receptor binding
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-KID / Tyrosine-protein phosphatase non-receptor type 11
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3 Å
AuthorsLuo, Y. / Zhu, J. / Yu, K. / Liu, B.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: To Be Published
Title: Small-molecule Allosteric Regulation Mechanism of SHP2
Authors: Luo, Y. / Zhu, J. / Yu, K. / Liu, B.
History
DepositionSep 17, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Sep 20, 2023Provider: 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)121,3374
Polymers120,4962
Non-polymers8412
Water0
1
A: Tyrosine-protein phosphatase non-receptor type 11
hetero molecules


Theoretical massNumber of molelcules
Total (without water)60,6682
Polymers60,2481
Non-polymers4201
Water0
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)60,6682
Polymers60,2481
Non-polymers4201
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)56.499, 91.170, 213.570
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 / SH-PTP2 / SHP-2 / Shp2


Mass: 60247.957 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SHPTP2 / Production host: Escherichia coli (E. coli) / References: UniProt: Q06124, protein-tyrosine-phosphatase
#2: Chemical ChemComp-KID / 2-[4-(aminomethyl)-4-methyl-piperidin-1-yl]-5-[2,3-bis(chloranyl)phenyl]-3-methyl-pyrrolo[2,1-f][1,2,4]triazin-4-one


Mass: 420.336 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H23Cl2N5O / Feature type: SUBJECT OF INVESTIGATION
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: 2.28 Å3/Da / Density % sol: 46.11 %
Crystal growTemperature: 295 K / Method: vapor diffusion, sitting drop / Details: 0.1 M Tris-HCl, pH 8.5, 13%-18% PEG 4000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL18U1 / Wavelength: 0.9793 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Oct 16, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9793 Å / Relative weight: 1
ReflectionResolution: 3→91.17 Å / Num. obs: 22835 / % possible obs: 99.6 % / Redundancy: 6.2 % / CC1/2: 0.977 / Net I/σ(I): 5.6
Reflection shellResolution: 3→3.18 Å / Num. unique obs: 3589 / CC1/2: 0.927

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Processing

Software
NameVersionClassification
PHENIX1.19.2_4158refinement
PDB_EXTRACT3.27data extraction
AUTOMARdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6WU8

6wu8


Resolution: 3→38.81 Å / SU ML: 0.4 / Cross valid method: THROUGHOUT / σ(F): 0 / Phase error: 34.98 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2877 1862 8.76 %
Rwork0.2397 19405 -
obs0.2439 21267 92.92 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 82.54 Å2 / Biso mean: 32.5762 Å2 / Biso min: 8.71 Å2
Refinement stepCycle: final / Resolution: 3→38.81 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7330 0 56 0 7386
Biso mean--37.35 --
Num. residues----955
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 13

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
3-3.080.41161230.30771333145685
3.08-3.170.32531290.29611357148686
3.17-3.270.34861280.27921388151688
3.27-3.390.33231360.27151409154590
3.39-3.530.35221460.26751482162893
3.53-3.690.25521470.24991488163594
3.69-3.880.30121440.22091476162094
3.88-4.120.26931450.22561519166495
4.12-4.440.2681480.20371547169597
4.44-4.890.23411500.19631543169396
4.89-5.590.25871530.22081585173897
5.59-7.040.26121540.25331617177198
7.04-38.810.29931590.24241661182096

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