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- PDB-7xhq: Small-molecule Allosteric Regulation Mechanism of SHP2 -

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Basic information

Entry
Database: PDB / ID: 7xhq
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 / 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 / face morphogenesis / Signal regulatory protein family interactions / ERBB signaling pathway / platelet formation / Interleukin-20 family signaling / Interleukin-6 signaling / triglyceride metabolic process / organ growth / megakaryocyte development / peptide hormone receptor binding / negative regulation of type I interferon production / PI-3K cascade:FGFR3 / Co-inhibition by CTLA4 / MAPK3 (ERK1) activation / Platelet sensitization by LDL / STAT5 activation downstream of FLT3 ITD mutants / PI-3K cascade:FGFR2 / PI-3K cascade:FGFR4 / PI-3K cascade:FGFR1 / MAPK1 (ERK2) activation / Prolactin receptor signaling / regulation of cell adhesion mediated by integrin / regulation of type I interferon-mediated signaling pathway / PECAM1 interactions / inner ear development / neurotrophin TRK receptor signaling pathway / Bergmann glial cell differentiation / Regulation of IFNA/IFNB signaling / positive regulation of intracellular signal transduction / peptidyl-tyrosine dephosphorylation / platelet-derived growth factor receptor signaling pathway / phosphoprotein phosphatase activity / RET signaling / Interleukin-3, Interleukin-5 and GM-CSF signaling / PI3K Cascade / ephrin receptor signaling pathway / Co-inhibition by PD-1 / fibroblast growth factor receptor signaling pathway / GAB1 signalosome / regulation of protein-containing complex assembly / Activated NTRK2 signals through FRS2 and FRS3 / positive regulation of insulin receptor signaling pathway / Regulation of IFNG signaling / negative regulation of insulin secretion / Signaling by CSF3 (G-CSF) / FRS-mediated FGFR3 signaling / Signaling by FLT3 ITD and TKD mutants / GPVI-mediated activation cascade / cell adhesion molecule binding / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / Tie2 Signaling / FRS-mediated FGFR1 signaling / homeostasis of number of cells within a tissue / hormone-mediated signaling pathway / negative regulation of T cell proliferation / T cell costimulation / FLT3 Signaling / phosphotyrosine residue binding / protein tyrosine phosphatase activity / protein-tyrosine-phosphatase / protein tyrosine phosphatase activity, metal-dependent / histone H2AXY142 phosphatase activity / non-membrane spanning protein tyrosine phosphatase activity / Downstream signal transduction / positive regulation of mitotic cell cycle / cellular response to epidermal growth factor stimulus / axonogenesis / positive regulation of interferon-beta production / protein tyrosine kinase binding / DNA damage checkpoint signaling / Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE) / integrin-mediated signaling pathway / positive regulation of D-glucose import / Negative regulation of FGFR3 signaling / insulin receptor binding / Negative regulation of FGFR2 signaling / Negative regulation of FGFR4 signaling
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-FIZ / Tyrosine-protein phosphatase non-receptor type 11
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsLuo, Y. / Zhu, J. / Yu, K. / Liu, B.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J Enzyme Inhib Med Chem / Year: 2023
Title: Discovery of the SHP2 allosteric inhibitor 2-((3R,4R)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-5-(2,3-dichlorophenyl)-3-methylpyrrolo[2,1-f][1,2,4] triazin-4(3H)-one.
Authors: Luo, Y. / Li, J. / Zong, Y. / Sun, M. / Zheng, W. / Zhu, J. / Liu, L. / Liu, B.
History
DepositionApr 9, 2022Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Feb 15, 2023Provider: repository / Type: Initial release
Revision 1.1Nov 29, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.2Oct 23, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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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)121,4214
Polymers120,4962
Non-polymers9252
Water8,467470
1
A: Tyrosine-protein phosphatase non-receptor type 11
hetero molecules


Theoretical massNumber of molelcules
Total (without water)60,7102
Polymers60,2481
Non-polymers4621
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)60,7102
Polymers60,2481
Non-polymers4621
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)55.690, 91.390, 212.979
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-FIZ / 2-[(3S,4R)-4-azanyl-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-5-[2,3-bis(chloranyl)phenyl]-3-methyl-pyrrolo[2,1-f][1,2,4]triazin-4-one


Mass: 462.372 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H25Cl2N5O2
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 470 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 2.25 Å3/Da / Density % sol: 45.31 %
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: BL19U1 / Wavelength: 0.9793 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 24, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9793 Å / Relative weight: 1
ReflectionResolution: 2.2→39.51 Å / Num. obs: 56019 / % possible obs: 99.6 % / Redundancy: 5.1 % / CC1/2: 0.993 / Net I/σ(I): 4.6
Reflection shellResolution: 2.2→2.26 Å / Num. unique obs: 4519 / CC1/2: 0.728

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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: 2.2→38.61 Å / SU ML: 0.3 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 34.48 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2746 1999 3.58 %
Rwork0.2388 53820 -
obs0.2401 55819 99.28 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 83.61 Å2 / Biso mean: 34.8876 Å2 / Biso min: 11.63 Å2
Refinement stepCycle: final / Resolution: 2.2→38.61 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7132 0 62 470 7664
Biso mean--33.49 39.79 -
Num. residues----946
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 14

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.2-2.250.35521420.337738053947100
2.26-2.320.33771420.31963823396599
2.32-2.380.36781390.31083767390699
2.38-2.460.35571400.29383777391799
2.46-2.550.33671420.28223830397299
2.55-2.650.2961420.26453790393299
2.65-2.770.30821400.25283792393299
2.77-2.920.25991400.23443788392899
2.92-3.10.28431420.23523802394499
3.1-3.340.25771430.225838584001100
3.34-3.680.26381440.21413862400699
3.68-4.210.22271450.199838864031100
4.21-5.30.24771460.192139454091100
5.3-38.610.24051520.24794095424799

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