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- PDB-7r7i: Structure of human SHP2 in complex with compound 27 -

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Basic information

Entry
Database: PDB / ID: 7r7i
TitleStructure of human SHP2 in complex with compound 27
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 / multicellular organismal reproductive process / atrioventricular canal development / negative regulation of cell adhesion mediated by integrin / STAT5 Activation / Netrin mediated repulsion signals ...negative regulation of cortisol secretion / intestinal epithelial cell migration / microvillus organization / negative regulation of growth hormone secretion / genitalia development / multicellular organismal reproductive process / 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 / Interleukin-37 signaling / regulation of protein export from nucleus / positive regulation of ossification / hormone metabolic process / Signaling by Leptin / MET activates PTPN11 / negative regulation of chondrocyte differentiation / Regulation of RUNX1 Expression and Activity / face morphogenesis / Costimulation by the CD28 family / triglyceride metabolic process / ERBB signaling pathway / Signal regulatory protein family interactions / organ growth / platelet formation / megakaryocyte development / negative regulation of type I interferon production / peptide hormone receptor binding / Platelet sensitization by LDL / CTLA4 inhibitory signaling / PI-3K cascade:FGFR2 / Interleukin-20 family signaling / PI-3K cascade:FGFR3 / Interleukin-6 signaling / STAT5 activation downstream of FLT3 ITD mutants / PI-3K cascade:FGFR4 / Prolactin receptor signaling / MAPK3 (ERK1) activation / PI-3K cascade:FGFR1 / PECAM1 interactions / regulation of cell adhesion mediated by integrin / MAPK1 (ERK2) activation / regulation of type I interferon-mediated signaling pathway / Bergmann glial cell differentiation / neurotrophin TRK receptor signaling pathway / inner ear development / phosphoprotein phosphatase activity / platelet-derived growth factor receptor signaling pathway / non-membrane spanning protein tyrosine phosphatase activity / PI3K Cascade / RET signaling / peptidyl-tyrosine dephosphorylation / Interleukin-3, Interleukin-5 and GM-CSF signaling / Regulation of IFNA/IFNB signaling / fibroblast growth factor receptor signaling pathway / regulation of protein-containing complex assembly / ephrin receptor signaling pathway / PD-1 signaling / GAB1 signalosome / Activated NTRK2 signals through FRS2 and FRS3 / negative regulation of insulin secretion / Regulation of IFNG signaling / Signaling by CSF3 (G-CSF) / positive regulation of insulin receptor signaling pathway / cell adhesion molecule binding / FRS-mediated FGFR2 signaling / FRS-mediated FGFR3 signaling / Signaling by FLT3 ITD and TKD mutants / FRS-mediated FGFR4 signaling / homeostasis of number of cells within a tissue / GPVI-mediated activation cascade / Tie2 Signaling / FRS-mediated FGFR1 signaling / FLT3 Signaling / T cell costimulation / cellular response to epidermal growth factor stimulus / phosphotyrosine residue binding / protein dephosphorylation / positive regulation of interferon-beta production / hormone-mediated signaling pathway / protein tyrosine kinase binding / Downstream signal transduction / positive regulation of mitotic cell cycle / axonogenesis / protein-tyrosine-phosphatase / Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE) / protein tyrosine phosphatase activity / DNA damage checkpoint signaling / integrin-mediated signaling pathway / positive regulation of D-glucose import / Negative regulation of FGFR2 signaling / Negative regulation of FGFR3 signaling / Negative regulation of FGFR4 signaling / insulin receptor binding / Negative regulation of FGFR1 signaling / Spry regulation of FGF signaling / brain development / epidermal growth factor receptor signaling pathway
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-3CW / Tyrosine-protein phosphatase non-receptor type 11
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.85 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
B: Tyrosine-protein phosphatase non-receptor type 11
hetero molecules


Theoretical massNumber of molelcules
Total (without water)123,7454
Polymers122,9832
Non-polymers7632
Water1086
1
A: Tyrosine-protein phosphatase non-receptor type 11
hetero molecules


Theoretical massNumber of molelcules
Total (without water)61,8732
Polymers61,4911
Non-polymers3811
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)61,8732
Polymers61,4911
Non-polymers3811
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)55.180, 83.630, 217.490
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 / Protein-tyrosine phosphatase 1D / PTP-1D / Protein-tyrosine phosphatase 2C / PTP-2C / SH-PTP2 / Shp2 / SH-PTP3


Mass: 61491.398 Da / Num. of mol.: 2
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-3CW / [3-(4-amino-4-methylpiperidin-1-yl)-6-(2,3-dichlorophenyl)-5-methylpyrazin-2-yl]methanol


Mass: 381.299 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H22Cl2N4O / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 6 / 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: 2.04 Å3/Da / Density % sol: 39.71 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / 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: APS / Beamline: 22-ID / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Apr 8, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.85→54.78 Å / Num. obs: 24328 / % possible obs: 99.8 % / Redundancy: 6 % / Biso Wilson estimate: 42.74 Å2 / CC1/2: 0.947 / Rmerge(I) obs: 0.334 / Rpim(I) all: 0.147 / Rrim(I) all: 0.365 / Net I/σ(I): 5.8 / Num. measured all: 146700 / Scaling rejects: 379
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
2.85-36.31.8472190834690.3910.7942.0151.899.8
9.01-54.785.20.08445648770.90.0430.09512.899

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Phasing

PhasingMethod: molecular replacement
Phasing MR
Highest resolutionLowest resolution
Rotation5.23 Å54.78 Å
Translation5.23 Å54.78 Å

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Processing

Software
NameVersionClassification
iMOSFLMdata reduction
Aimless0.6.3data scaling
PHASER2.7.16phasing
PHENIX1.19.1-4122-000refinement
PDB_EXTRACT3.27data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2SHP

2shp


Resolution: 2.85→54.78 Å / SU ML: 0.39 / Cross valid method: THROUGHOUT / σ(F): 1.33 / Phase error: 30.6 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2917 1292 5.33 %
Rwork0.2315 22962 -
obs0.2348 24254 99.59 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 101.71 Å2 / Biso mean: 40.3504 Å2 / Biso min: 11.82 Å2
Refinement stepCycle: final / Resolution: 2.85→54.78 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7908 0 50 6 7964
Biso mean--36.21 34.74 -
Num. residues----977
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0038123
X-RAY DIFFRACTIONf_angle_d0.5410957
X-RAY DIFFRACTIONf_dihedral_angle_d10.0021083
X-RAY DIFFRACTIONf_chiral_restr0.0421174
X-RAY DIFFRACTIONf_plane_restr0.0041411
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 9

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.85-2.960.39251280.33442493262199
2.96-3.10.39181660.301225022668100
3.1-3.260.34791400.270625152655100
3.26-3.470.31851630.264225062669100
3.47-3.730.2851240.231125402664100
3.73-4.110.28981450.210325322677100
4.11-4.70.25561350.18372562269799
4.7-5.930.2121440.19742592273699
5.93-54.780.28041470.22422720286799

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