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- PDB-7r75: Structure of human SHP2 in complex with compound 16 -

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Basic information

Entry
Database: PDB / ID: 7r75
TitleStructure of human SHP2 in complex with compound 16
ComponentsTyrosine-protein phosphatase non-receptor type 11
KeywordsHYDROLASE/INHIBITOR / Phosphatase / Inhibitor / Shp2 / Allosteric / 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 / Netrin mediated repulsion signals / cerebellar cortex formation ...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 / 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 / Regulation of T cell activation by CD28 family / Signal regulatory protein family interactions / ERBB signaling pathway / platelet formation / megakaryocyte development / triglyceride metabolic process / negative regulation of type I interferon production / organ growth / peptide hormone receptor binding / Interleukin-20 family signaling / Co-inhibition by CTLA4 / Platelet sensitization by LDL / PI-3K cascade:FGFR3 / Interleukin-6 signaling / STAT5 activation downstream of FLT3 ITD mutants / PI-3K cascade:FGFR2 / PI-3K cascade:FGFR4 / MAPK3 (ERK1) activation / PI-3K cascade:FGFR1 / Prolactin receptor signaling / regulation of cell adhesion mediated by integrin / regulation of type I interferon-mediated signaling pathway / MAPK1 (ERK2) activation / inner ear development / neurotrophin TRK receptor signaling pathway / PECAM1 interactions / Bergmann glial cell differentiation / platelet-derived growth factor receptor signaling pathway / phosphoprotein phosphatase activity / RET signaling / peptidyl-tyrosine dephosphorylation / non-membrane spanning protein tyrosine phosphatase activity / Regulation of IFNA/IFNB signaling / Interleukin-3, Interleukin-5 and GM-CSF signaling / PI3K Cascade / ephrin receptor signaling pathway / Co-inhibition by PD-1 / 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 / homeostasis of number of cells within a tissue / GPVI-mediated activation cascade / Tie2 Signaling / FRS-mediated FGFR1 signaling / cell adhesion molecule binding / T cell costimulation / hormone-mediated signaling pathway / FLT3 Signaling / cellular response to epidermal growth factor stimulus / positive regulation of interferon-beta production / phosphotyrosine residue binding / Downstream signal transduction / positive regulation of mitotic cell cycle / protein-tyrosine-phosphatase / axonogenesis / protein tyrosine kinase binding / protein tyrosine phosphatase activity / Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE) / DNA damage checkpoint signaling / positive regulation of D-glucose import / integrin-mediated signaling pathway / Negative regulation of FGFR3 signaling / insulin receptor binding / Negative regulation of FGFR2 signaling / 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 / brain development / multicellular organism growth
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-33I / Tyrosine-protein phosphatase non-receptor type 11
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.83 Å
AuthorsLeonard, P.G. / Cross, J.
CitationJournal: J.Med.Chem. / Year: 2021
Title: Discovery of 6-[(3 S ,4 S )-4-Amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl]-3-(2,3-dichlorophenyl)-2-methyl-3,4-dihydropyrimidin-4-one (IACS-15414), a Potent and Orally Bioavailable SHP2 Inhibitor.
Authors: Czako, B. / Sun, Y. / McAfoos, T. / Cross, J.B. / Leonard, P.G. / Burke, J.P. / Carroll, C.L. / Feng, N. / Harris, A.L. / Jiang, Y. / Kang, Z. / Kovacs, J.J. / Mandal, P. / Meyers, B.A. / ...Authors: Czako, B. / Sun, Y. / McAfoos, T. / Cross, J.B. / Leonard, P.G. / Burke, J.P. / Carroll, C.L. / Feng, N. / Harris, A.L. / Jiang, Y. / Kang, Z. / Kovacs, J.J. / Mandal, P. / Meyers, B.A. / Mseeh, F. / Parker, C.A. / Yu, S.S. / Williams, C.C. / Wu, Q. / Di Francesco, M.E. / Draetta, G. / Heffernan, T. / Marszalek, J.R. / Kohl, N.E. / Jones, P.
History
DepositionJun 24, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 27, 2021Provider: repository / Type: Initial release
Revision 1.1Nov 10, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Oct 18, 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

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Assembly

Deposited unit
A: Tyrosine-protein phosphatase non-receptor type 11
hetero molecules


Theoretical massNumber of molelcules
Total (without water)61,8502
Polymers61,4911
Non-polymers3591
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area22080 Å2
Unit cell
Length a, b, c (Å)39.620, 53.350, 215.840
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP22121

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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 / Shp2 / SH-PTP3


Mass: 61491.398 Da / Num. of mol.: 1
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-33I / 6-(4-amino-4-methylpiperidin-1-yl)-3-(3-chlorophenyl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one


Mass: 358.825 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H19ClN6O / 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

Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 8 / Details: 300 mM potassium formate, 14% w/v PEG3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 8.3.1 / Wavelength: 1.115867 Å
DetectorType: ADSC QUANTUM 315r / Detector: CCD / Date: Jan 23, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.115867 Å / Relative weight: 1
ReflectionResolution: 2.83→53.96 Å / Num. obs: 10445 / % possible obs: 89.3 % / Redundancy: 6.8 % / Biso Wilson estimate: 48.24 Å2 / CC1/2: 0.99 / Rmerge(I) obs: 0.2 / Rpim(I) all: 0.079 / Rrim(I) all: 0.216 / Net I/σ(I): 8 / Num. measured all: 71394 / Scaling rejects: 11
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.83-2.986.81.158982614470.640.4661.2521.787.9
8.94-53.9680.06135874500.9980.0210.06421.999.9

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation6.93 Å53.96 Å
Translation6.93 Å53.96 Å

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Processing

Software
NameVersionClassification
iMOSFLMdata reduction
Aimless0.3.11data scaling
PHASER2.5.6phasing
PHENIX1.19.1-4122-000refinement
PDB_EXTRACT3.27data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2SHP

2shp


Resolution: 2.83→53.96 Å / SU ML: 0.27 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 26.62 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2889 568 5.46 %
Rwork0.2249 9829 -
obs0.2283 10397 89.29 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 102.44 Å2 / Biso mean: 45.1935 Å2 / Biso min: 16.76 Å2
Refinement stepCycle: final / Resolution: 2.83→53.96 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3993 0 25 0 4018
Biso mean--35.12 --
Num. residues----494
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0024099
X-RAY DIFFRACTIONf_angle_d0.4665527
X-RAY DIFFRACTIONf_dihedral_angle_d14.0671542
X-RAY DIFFRACTIONf_chiral_restr0.04592
X-RAY DIFFRACTIONf_plane_restr0.003714
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 4

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.83-3.110.37191170.29452334245187
3.11-3.560.29751610.252307246886
3.56-4.480.30651340.2062380251487
4.49-53.960.24921560.2072808296497

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