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- PDB-7vxg: Non-receptor Protein Tyrosine Phosphatase SHP2 in Complex with Al... -

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Basic information

Entry
Database: PDB / ID: 7vxg
TitleNon-receptor Protein Tyrosine Phosphatase SHP2 in Complex with Allosteric Inhibitor TK-453
ComponentsTyrosine-protein phosphatase non-receptor type 11
KeywordsANTITUMOR PROTEIN / Protein tyrosine phosphatase / SHP2 / 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 / cerebellar cortex formation / negative regulation of neutrophil activation / positive regulation of hormone secretion / regulation of protein export from nucleus / positive regulation of ossification / positive regulation of lipopolysaccharide-mediated signaling pathway / Interleukin-37 signaling / Signaling by Leptin / hormone metabolic process / MET activates PTPN11 / 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 / organ growth / negative regulation of type I interferon production / Interleukin-20 family signaling / PI-3K cascade:FGFR3 / Interleukin-6 signaling / 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 / MAPK3 (ERK1) activation / PI-3K cascade:FGFR1 / Prolactin receptor signaling / neurotrophin TRK receptor signaling pathway / regulation of cell adhesion mediated by integrin / platelet-derived growth factor receptor signaling pathway / regulation of type I interferon-mediated signaling pathway / MAPK1 (ERK2) activation / 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 / RET signaling / Regulation of IFNA/IFNB signaling / Interleukin-3, Interleukin-5 and GM-CSF signaling / PI3K Cascade / Co-inhibition by PD-1 / fibroblast growth factor receptor signaling pathway / GAB1 signalosome / positive regulation of insulin receptor signaling pathway / ephrin receptor signaling pathway / regulation of protein-containing complex assembly / Activated NTRK2 signals through FRS2 and FRS3 / Regulation of IFNG signaling / cell adhesion molecule binding / FRS-mediated FGFR3 signaling / Signaling by CSF3 (G-CSF) / GPVI-mediated activation cascade / Signaling by FLT3 ITD and TKD mutants / negative regulation of T cell proliferation / T cell costimulation / FRS-mediated FGFR2 signaling / hormone-mediated signaling pathway / FRS-mediated FGFR4 signaling / Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE) / FRS-mediated FGFR1 signaling / Tie2 Signaling / phosphotyrosine residue binding / FLT3 Signaling / protein-tyrosine-phosphatase / homeostasis of number of cells within a tissue / Downstream signal transduction / axonogenesis / positive regulation of mitotic cell cycle / positive regulation of interferon-beta production / protein tyrosine phosphatase activity / protein tyrosine kinase binding / Negative regulation of FGFR3 signaling / cellular response to epidermal growth factor stimulus / Negative regulation of FGFR2 signaling / DNA damage checkpoint signaling / Negative regulation of FGFR4 signaling / Negative regulation of FGFR1 signaling / Spry regulation of FGF signaling / integrin-mediated signaling pathway / positive regulation of D-glucose import / insulin receptor binding / negative regulation of insulin secretion
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-83Q / Tyrosine-protein phosphatase non-receptor type 11
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.1 Å
AuthorsLi, T.H. / Guo, H.T. / Ji, X.Y.
Funding support China, 3items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)81872877 China
National Natural Science Foundation of China (NSFC)91853109 China
National Natural Science Foundation of China (NSFC)81773562 China
CitationJournal: Iscience / Year: 2022
Title: SHP2 allosteric inhibitor TK-453 alleviates psoriasis-like skin inflammation in mice via inhibition of IL-23/Th17 axis.
Authors: Wang, M. / Li, T. / Ouyang, Z. / Tang, K. / Zhu, Y. / Song, C. / Sun, H. / Yu, B. / Ji, X. / Sun, Y.
History
DepositionNov 12, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Mar 23, 2022Provider: repository / Type: Initial release
Revision 1.1Apr 6, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Nov 29, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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
C: Tyrosine-protein phosphatase non-receptor type 11
D: Tyrosine-protein phosphatase non-receptor type 11
hetero molecules


Theoretical massNumber of molelcules
Total (without water)242,9348
Polymers241,3404
Non-polymers1,5934
Water6,846380
1
A: Tyrosine-protein phosphatase non-receptor type 11
hetero molecules


Theoretical massNumber of molelcules
Total (without water)60,7332
Polymers60,3351
Non-polymers3981
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)60,7332
Polymers60,3351
Non-polymers3981
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Tyrosine-protein phosphatase non-receptor type 11
hetero molecules


Theoretical massNumber of molelcules
Total (without water)60,7332
Polymers60,3351
Non-polymers3981
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Tyrosine-protein phosphatase non-receptor type 11
hetero molecules


Theoretical massNumber of molelcules
Total (without water)60,7332
Polymers60,3351
Non-polymers3981
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)45.403, 55.596, 218.839
Angle α, β, γ (deg.)88.66, 102.01, 96.19
Int Tables number1
Space group name H-MP1

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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 / SHP- ...Protein-tyrosine phosphatase 1D / PTP-1D / Protein-tyrosine phosphatase 2C / PTP-2C / SH-PTP2 / SHP-2 / Shp2 / SH-PTP3


Mass: 60335.035 Da / Num. of mol.: 4
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-83Q / 6-[4-(aminomethyl)-4-methyl-piperidin-1-yl]-3-[2,3-bis(chloranyl)phenyl]sulfanyl-pyrazin-2-amine


Mass: 398.353 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C17H21Cl2N5S / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 380 / 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: 2.23 Å3/Da / Density % sol: 44.74 %
Crystal growTemperature: 295 K / Method: vapor diffusion, sitting drop / pH: 8.2
Details: 100mM Tris-HCl pH 8.2, 12% (vol/vol) PEG 4000, 20mM DTT

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL17U1 / Wavelength: 0.979 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Jan 23, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.1→50 Å / Num. obs: 101938 / % possible obs: 83.83 % / Redundancy: 3.1 % / Biso Wilson estimate: 27.17 Å2 / Rrim(I) all: 0.2 / Net I/σ(I): 7.1
Reflection shellResolution: 2.1→2.14 Å / Num. unique obs: 9746 / CC1/2: 0.451

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Processing

Software
NameVersionClassification
PHENIX(1.19.2_4158: ???)refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2SHP

2shp


Resolution: 2.1→38.14 Å / SU ML: 0.39 / Cross valid method: FREE R-VALUE / σ(F): 1.96 / Phase error: 36.87 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.3249 1994 1.96 %
Rwork0.2698 --
obs0.2709 101849 83.72 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.1→38.14 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms15106 0 100 380 15586
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01415521
X-RAY DIFFRACTIONf_angle_d1.25621063
X-RAY DIFFRACTIONf_dihedral_angle_d8.9652116
X-RAY DIFFRACTIONf_chiral_restr0.0642320
X-RAY DIFFRACTIONf_plane_restr0.0122731
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.1-2.150.40471270.32766616X-RAY DIFFRACTION77
2.15-2.210.34131400.30516977X-RAY DIFFRACTION83
2.21-2.270.33721350.3026868X-RAY DIFFRACTION80
2.27-2.350.31181370.28836876X-RAY DIFFRACTION81
2.35-2.430.38291450.29486964X-RAY DIFFRACTION82
2.43-2.530.36621390.30046875X-RAY DIFFRACTION80
2.53-2.640.40761330.30296897X-RAY DIFFRACTION81
2.64-2.780.37511310.29636756X-RAY DIFFRACTION79
2.78-2.960.34331390.28476916X-RAY DIFFRACTION81
2.96-3.190.32621440.27486970X-RAY DIFFRACTION82
3.19-3.510.35911460.25997360X-RAY DIFFRACTION86
3.51-4.010.28251520.2427678X-RAY DIFFRACTION90
4.01-5.050.26921600.22757914X-RAY DIFFRACTION92
5.05-38.140.31311660.2758188X-RAY DIFFRACTION97
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)
16.1095-0.544-1.99915.7210.18845.8339-0.50290.3913-0.4524-0.07080.0650.38430.6876-0.9960.40340.4858-0.00530.08490.4758-0.04380.294824.037942.992846.9713
20.9073-0.0246-0.56110.5998-0.43022.5713-0.0463-0.0893-0.12940.1891-0.05530.040.2683-0.21040.07950.49060.01160.00520.2714-0.00030.225840.455237.084647.8517
31.46251.0368-0.51632.2021-0.57762.1466-0.09230.064-0.0549-0.30920.0372-0.04790.0083-0.05560.05270.34790.06790.01110.1664-0.01150.169951.054842.016222.0107
45.40281.1986-1.32464.71380.89463.6536-0.2224-0.3372-0.41970.09410.3121-0.59-0.03551.2959-0.00530.2947-0.0178-0.00430.5784-0.00730.280558.089223.7095-23.2733
50.521-0.28080.19220.41110.46551.30410.0412-0.17870.54320.081-0.2528-0.2873-0.34720.9325-0.0430.0544-0.14280.01280.47850.03870.321849.273629.2321-15.436
60.98760.4036-0.53621.52690.18861.7249-0.21060.153-0.1632-0.107-0.0772-0.1070.49260.17180.26710.68610.19320.03110.3671-0.03270.291946.93454.185-31.3297
71.4517-0.4493-0.61080.86310.46891.7509-0.08970.0221-0.07890.0947-0.00310.0330.0150.05370.08050.4172-0-0.00260.1685-0.00410.189131.679919.1555-1.4822
82.7061-1.00251.10652.26280.92563.24950.06830.0845-0.0988-0.02340.0824-0.3138-0.15290.90890.04090.25740.0427-0.01320.40860.02410.285154.03713.9998152.2545
91.0803-0.70920.5470.6126-0.16823.4818-0.2402-0.21320.29580.1522-0.0566-0.0332-0.55870.08950.15840.8522-0.0249-0.07370.2815-0.07930.374841.767336.5484163.4797
101.92051.2460.11244.82550.71211.39750.2038-0.3664-0.02970.5092-0.2089-0.05750.34130.00970.0130.34570.0567-0.03470.24060.01580.150239.683914.1882147.6574
112.90910.0875-0.00223.55980.20411.8551-0.28080.1247-0.26630.0035-0.03760.36240.6852-0.16850.05790.47910.05330.00550.2255-0.0450.229229.0145.5545139.2075
121.33680.73540.45531.94930.64511.8783-0.07620.00050.0685-0.26170.00490.025-0.08910.04640.07680.40390.05820.00290.15770.00240.174131.06417.845128.6963
133.57210.98432.04136.1340.68165.9794-0.2774-0.42990.18250.16320.00350.60050.1713-1.240.27540.4288-0.04160.00130.6007-0.04460.260624.538535.919983.8388
140.96760.09990.70121.9455-0.69942.2429-0.06660.06320.0814-0.2382-0.19340.1126-0.4861-0.44970.15580.49120.137-0.00090.3946-0.03240.22333.895747.074177.5805
151.4154-0.4750.71481.1961-0.10652.2042-0.06730.02730.09330.07690.00940.0343-0.0771-0.03340.05310.3127-0.01150.02190.15450.01260.166149.601441.9488104.12
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 3 through 47 )
2X-RAY DIFFRACTION2chain 'A' and (resid 48 through 310 )
3X-RAY DIFFRACTION3chain 'A' and (resid 311 through 525 )
4X-RAY DIFFRACTION4chain 'B' and (resid 4 through 47 )
5X-RAY DIFFRACTION5chain 'B' and (resid 48 through 83 )
6X-RAY DIFFRACTION6chain 'B' and (resid 84 through 246 )
7X-RAY DIFFRACTION7chain 'B' and (resid 247 through 525 )
8X-RAY DIFFRACTION8chain 'C' and (resid 3 through 112 )
9X-RAY DIFFRACTION9chain 'C' and (resid 113 through 245 )
10X-RAY DIFFRACTION10chain 'C' and (resid 246 through 276 )
11X-RAY DIFFRACTION11chain 'C' and (resid 277 through 334 )
12X-RAY DIFFRACTION12chain 'C' and (resid 335 through 525 )
13X-RAY DIFFRACTION13chain 'D' and (resid 3 through 47 )
14X-RAY DIFFRACTION14chain 'D' and (resid 48 through 209 )
15X-RAY DIFFRACTION15chain 'D' and (resid 210 through 525 )

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