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- PDB-8b5y: SHP2 in complex with allosteric imidazopyrazine inhibitor -

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Basic information

Entry
Database: PDB / ID: 8b5y
TitleSHP2 in complex with allosteric imidazopyrazine inhibitor
ComponentsTyrosine-protein phosphatase non-receptor type 11
KeywordsSIGNALING PROTEIN / SHP2 / allosteric inhibitors / imidazopyrazine / oncology
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 / positive regulation of hormone secretion ...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 / positive regulation of hormone secretion / cerebellar cortex formation / multicellular organismal reproductive process / regulation of protein export from nucleus / positive regulation of ossification / hormone metabolic process / Interleukin-37 signaling / Signaling by Leptin / negative regulation of chondrocyte differentiation / MET activates PTPN11 / Regulation of RUNX1 Expression and Activity / face morphogenesis / ERBB signaling pathway / Costimulation by the CD28 family / Signal regulatory protein family interactions / peptide hormone receptor binding / negative regulation of type I interferon production / platelet formation / megakaryocyte development / organ growth / CTLA4 inhibitory signaling / triglyceride metabolic process / Platelet sensitization by LDL / Interleukin-20 family signaling / PI-3K cascade:FGFR3 / Interleukin-6 signaling / STAT5 activation downstream of FLT3 ITD mutants / PI-3K cascade:FGFR2 / PI-3K cascade:FGFR4 / Prolactin receptor signaling / PI-3K cascade:FGFR1 / MAPK3 (ERK1) activation / PECAM1 interactions / MAPK1 (ERK2) activation / regulation of cell adhesion mediated by integrin / regulation of type I interferon-mediated signaling pathway / Bergmann glial cell differentiation / phosphoprotein phosphatase activity / inner ear development / neurotrophin TRK receptor signaling pathway / platelet-derived growth factor receptor signaling pathway / non-membrane spanning protein tyrosine phosphatase activity / RET signaling / peptidyl-tyrosine dephosphorylation / Interleukin-3, Interleukin-5 and GM-CSF signaling / Regulation of IFNA/IFNB signaling / PI3K Cascade / PD-1 signaling / regulation of protein-containing complex assembly / ephrin receptor signaling pathway / 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 / homeostasis of number of cells within a tissue / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / Tie2 Signaling / FRS-mediated FGFR1 signaling / cellular response to epidermal growth factor stimulus / cell adhesion molecule binding / GPVI-mediated activation cascade / T cell costimulation / FLT3 Signaling / positive regulation of interferon-beta production / hormone-mediated signaling pathway / phosphotyrosine residue binding / positive regulation of mitotic cell cycle / Downstream signal transduction / protein dephosphorylation / Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE) / protein-tyrosine-phosphatase / axonogenesis / protein tyrosine kinase binding / DNA damage checkpoint signaling / protein tyrosine phosphatase activity / integrin-mediated signaling pathway / positive regulation of glucose import / Negative regulation of FGFR3 signaling / Negative regulation of FGFR2 signaling / Negative regulation of FGFR4 signaling / Negative regulation of FGFR1 signaling / Spry regulation of FGF signaling / insulin receptor binding / epidermal growth factor receptor signaling pathway / multicellular organism growth
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
FORMIC ACID / Chem-P8O / Tyrosine-protein phosphatase non-receptor type 11
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.83 Å
AuthorsTorrente, E. / Petrocchi, A.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Acs Med.Chem.Lett. / Year: 2023
Title: Discovery of a Novel Series of Imidazopyrazine Derivatives as Potent SHP2 Allosteric Inhibitors.
Authors: Torrente, E. / Fodale, V. / Ciammaichella, A. / Ferrigno, F. / Ontoria, J.M. / Ponzi, S. / Rossetti, I. / Sferrazza, A. / Amaudrut, J. / Missineo, A. / Esposito, S. / Palombo, S. / Nibbio, M. ...Authors: Torrente, E. / Fodale, V. / Ciammaichella, A. / Ferrigno, F. / Ontoria, J.M. / Ponzi, S. / Rossetti, I. / Sferrazza, A. / Amaudrut, J. / Missineo, A. / Esposito, S. / Palombo, S. / Nibbio, M. / Cerretani, M. / Bisbocci, M. / Cellucci, A. / di Marco, A. / Alli, C. / Pucci, V. / Toniatti, C. / Petrocchi, A.
History
DepositionSep 25, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 18, 2023Provider: repository / Type: Initial release
Revision 1.1Mar 1, 2023Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID / _citation_author.name
Revision 1.2Feb 7, 2024Group: 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)122,61826
Polymers120,6102
Non-polymers2,00824
Water15,205844
1
A: Tyrosine-protein phosphatase non-receptor type 11
hetero molecules


Theoretical massNumber of molelcules
Total (without water)61,40115
Polymers60,3051
Non-polymers1,09614
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)61,21711
Polymers60,3051
Non-polymers91210
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)51.908, 190.263, 57.297
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number4
Space group name H-MP1211

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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: 60305.004 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-P8O / (1~{S})-1'-[5-[2-(trifluoromethyl)pyridin-3-yl]sulfanyl-3~{H}-imidazo[4,5-b]pyrazin-2-yl]spiro[1,3-dihydroindene-2,4'-piperidine]-1-amine


Mass: 497.539 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C24H22F3N7S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical...
ChemComp-FMT / FORMIC ACID


Mass: 46.025 Da / Num. of mol.: 22 / Source method: isolated from a natural source / Formula: CH2O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 844 / 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: 2.44 Å3/Da / Density % sol: 49.58 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, hanging drop / pH: 8.5 / Details: 21.00 %w/v PEG 3350, 0.30 M K Form

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X6A / Wavelength: 0.999983 Å
DetectorType: DECTRIS EIGER2 S 16M / Detector: PIXEL / Date: Sep 7, 2019
RadiationMonochromator: M / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.999983 Å / Relative weight: 1
ReflectionResolution: 1.45→95.13 Å / Num. obs: 97403 / % possible obs: 96 % / Redundancy: 2.3 % / CC1/2: 0.779 / Rmerge(I) obs: 0.185 / Rpim(I) all: 0.147 / Net I/σ(I): 4.6
Reflection shellResolution: 1.45→1.455 Å / Redundancy: 1.9 % / Num. unique obs: 6235 / CC1/2: 0.022 / % possible all: 87.6

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Processing

Software
NameVersionClassification
REFMAC5.8.0155refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
pointlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4NWF, 4NWG

4nwf

4nwg


Resolution: 1.83→95.13 Å / Cor.coef. Fo:Fc: 0.965 / Cor.coef. Fo:Fc free: 0.941 / SU B: 6.346 / SU ML: 0.098 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.132 / ESU R Free: 0.127 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2182 2519 2.6 %RANDOM
Rwork0.1773 ---
obs0.1784 94468 99.57 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 99.66 Å2 / Biso mean: 33.608 Å2 / Biso min: 13.11 Å2
Baniso -1Baniso -2Baniso -3
1-1.58 Å20 Å2-0.23 Å2
2---1.16 Å2-0 Å2
3----0.42 Å2
Refinement stepCycle: final / Resolution: 1.83→95.13 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8154 0 136 846 9136
Biso mean--39.07 39.31 -
Num. residues----1008
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0198656
X-RAY DIFFRACTIONr_bond_other_d0.0030.028038
X-RAY DIFFRACTIONr_angle_refined_deg1.5611.95811720
X-RAY DIFFRACTIONr_angle_other_deg1.275318485
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.32351064
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.74124.223431
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.6615.0531512
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.4361561
X-RAY DIFFRACTIONr_chiral_restr0.0890.21245
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.0210000
X-RAY DIFFRACTIONr_gen_planes_other0.0020.022065
LS refinement shellResolution: 1.83→1.878 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.324 180 -
Rwork0.301 6992 -
all-7172 -
obs--99.92 %
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)
14.19611.54440.18353.88690.09271.56860.0036-0.07150.18570.11240.0243-0.3772-0.09180.1888-0.0280.0730.03060.0110.18810.00370.184339.8057.35522.357
23.90560.78491.45195.1910.61852.6739-0.15670.19250.1841-0.33810.13820.1212-0.0473-0.06590.01860.2234-0.02380.07160.16660.05630.145130.63622.356-4.09
31.36790.42-0.49351.6338-0.10251.7185-0.01630.04610.0027-0.05510.0076-0.0006-0.0065-0.09490.00860.00750.00970.00910.12260.00050.017315.322-7.75815.996
44.1963-1.2895-0.12674.3312-0.01731.34450.020.0932-0.1855-0.1524-0.0051-0.39860.0890.2041-0.01480.0724-0.02980.03490.1930.00140.180539.83549.2246.335
54.0981-0.7925-1.23074.89240.29612.4561-0.1454-0.1745-0.17350.36390.13620.06420.05-0.06550.00920.22410.0201-0.03820.17070.04680.130930.84134.18532.668
61.3487-0.4320.53421.5474-0.14771.8582-0.0199-0.0405-0.00650.06120.01610.00080.0055-0.10650.00390.0106-0.0090.01380.1194-0.00190.025115.33664.33812.666
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A3 - 109
2X-RAY DIFFRACTION2A110 - 218
3X-RAY DIFFRACTION3A219 - 999
4X-RAY DIFFRACTION4B3 - 109
5X-RAY DIFFRACTION5B110 - 218
6X-RAY DIFFRACTION6B219 - 999

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