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- PDB-8u7x: Crystal structure of non-receptor protein tyrosine phosphatase SH... -

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Basic information

Entry
Database: PDB / ID: 8u7x
TitleCrystal structure of non-receptor protein tyrosine phosphatase SHP2 in complex with inhibitor compound 24
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 / 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 / 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-WAB / Tyrosine-protein phosphatase non-receptor type 11
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.06 Å
AuthorsMou, T.C.
Funding support United States, 1items
OrganizationGrant numberCountry
Other private United States
CitationJournal: Acs Med.Chem.Lett. / Year: 2023
Title: Discovery of 5-Azaquinoxaline Derivatives as Potent and Orally Bioavailable Allosteric SHP2 Inhibitors.
Authors: Elsayed, M.S.A. / Blake, J.F. / Boys, M.L. / Brown, E. / Chapsal, B.D. / Chicarelli, M.J. / Cook, A.W. / Fell, J.B. / Fischer, J.P. / Hanson, L. / Lemieux, C. / Martinson, M.C. / McCown, J. ...Authors: Elsayed, M.S.A. / Blake, J.F. / Boys, M.L. / Brown, E. / Chapsal, B.D. / Chicarelli, M.J. / Cook, A.W. / Fell, J.B. / Fischer, J.P. / Hanson, L. / Lemieux, C. / Martinson, M.C. / McCown, J. / McNulty, O.T. / Mejia, M.J. / Neitzel, N.A. / Otten, J.N. / Rodriguez, M.E. / Wilcox, D. / Wong, C.E. / Zhou, Y. / Hinklin, R.J.
History
DepositionSep 15, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 3, 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)125,0964
Polymers124,1802
Non-polymers9162
Water11,962664
1
A: Tyrosine-protein phosphatase non-receptor type 11
hetero molecules


Theoretical massNumber of molelcules
Total (without water)62,5482
Polymers62,0901
Non-polymers4581
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Tyrosine-protein phosphatase non-receptor type 11
hetero molecules


Theoretical massNumber of molelcules
Total (without water)62,5482
Polymers62,0901
Non-polymers4581
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)45.440, 213.200, 55.770
Angle α, β, γ (deg.)90.000, 96.360, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb
Symmetry operation#1: x,y,z
#2: -x,y+1/2,-z

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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-WAB / (3S,4S)-8-{6-[(2-amino-3-chloropyridin-4-yl)sulfanyl]pyrido[2,3-b]pyrazin-2-yl}-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine


Mass: 457.980 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H24ClN7OS / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 664 / 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: 2.16 Å3/Da / Density % sol: 43.11 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 7.6
Details: 13% PEG3350, 0.1M Bicine, pH7.6, 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 / Wavelength: 1.54 Å
DetectorType: DECTRIS EIGER R 1M / Detector: PIXEL / Date: Nov 30, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2.06→30 Å / Num. obs: 63072 / % possible obs: 97.6 % / Redundancy: 6.3 % / Biso Wilson estimate: 24.61 Å2 / CC1/2: 0.996 / Rpim(I) all: 0.041 / Rrim(I) all: 0.105 / Net I/σ(I): 12
Reflection shellResolution: 2.06→2.17 Å / Redundancy: 5.2 % / Mean I/σ(I) obs: 4.9 / Num. unique obs: 9094 / CC1/2: 0.92 / Rpim(I) all: 0.141 / Rrim(I) all: 0.324 / % possible all: 96.4

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.06→27.71 Å / SU ML: 0.1891 / Cross valid method: FREE R-VALUE / σ(F): 0 / Phase error: 16.8856
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1752 1997 3.17 %
Rwork0.1684 60977 -
obs0.1686 62974 97.45 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 30.2 Å2
Refinement stepCycle: LAST / Resolution: 2.06→27.71 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8001 0 62 666 8729
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00218246
X-RAY DIFFRACTIONf_angle_d0.523511135
X-RAY DIFFRACTIONf_chiral_restr0.04221192
X-RAY DIFFRACTIONf_plane_restr0.00331439
X-RAY DIFFRACTIONf_dihedral_angle_d16.283128
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.06-2.110.23431380.20374197X-RAY DIFFRACTION95.25
2.11-2.170.19531420.18324340X-RAY DIFFRACTION96.64
2.17-2.230.19271400.17344307X-RAY DIFFRACTION96.86
2.23-2.310.22031400.17564290X-RAY DIFFRACTION96.22
2.31-2.390.20251430.17734343X-RAY DIFFRACTION96.91
2.39-2.480.19541410.17794286X-RAY DIFFRACTION96.68
2.48-2.60.18631410.17554334X-RAY DIFFRACTION96.84
2.6-2.730.19261430.17974346X-RAY DIFFRACTION97.25
2.73-2.90.20471420.17414348X-RAY DIFFRACTION97.08
2.9-3.130.18881450.17944430X-RAY DIFFRACTION99.26
3.13-3.440.17191480.16574474X-RAY DIFFRACTION99.76
3.44-3.940.1371450.15274455X-RAY DIFFRACTION99.48
3.94-4.960.14341450.1424439X-RAY DIFFRACTION99.01
4.96-27.710.16621440.17884388X-RAY DIFFRACTION97.07

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