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- PDB-8cbh: SHP2 in complex with a novel allosteric inhibitor -

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Basic information

Entry
Database: PDB / ID: 8cbh
TitleSHP2 in complex with a novel allosteric 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 / 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-U70 / Tyrosine-protein phosphatase non-receptor type 11
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.24 Å
Authorsdi Fabio, R. / Petrocchi, A.
Funding support1items
OrganizationGrant numberCountry
Not funded
Citation
Journal: 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.
#1: Journal: 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.
#2: Journal: Acs Med.Chem.Lett. / Year: 2023
Title: Discovery of a Novel Series of Potent SHP2 Allosteric Inhibitors
Authors: Petrocchi, A. / Grillo, A. / Ferrante, L. / Randazzo, P. / Prandi, A. / De Matteo, M. / Iaccarino, C. / Bisbocci, M. / Cellucci, A. / Alli, C. / Nibbio, M. / Pucci, V. / Amaudrut, J. / ...Authors: Petrocchi, A. / Grillo, A. / Ferrante, L. / Randazzo, P. / Prandi, A. / De Matteo, M. / Iaccarino, C. / Bisbocci, M. / Cellucci, A. / Alli, C. / Nibbio, M. / Pucci, V. / Amaudrut, J. / Montalbetti, C. / Toniatti, C. / Di Fabio, R.
History
DepositionJan 25, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 26, 2023Provider: repository / Type: Initial release
Revision 1.1Jun 19, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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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)121,5834
Polymers120,6102
Non-polymers9732
Water4,360242
1
A: Tyrosine-protein phosphatase non-receptor type 11
hetero molecules


Theoretical massNumber of molelcules
Total (without water)60,7912
Polymers60,3051
Non-polymers4861
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)60,7912
Polymers60,3051
Non-polymers4861
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)44.888, 215.966, 55.829
Angle α, β, γ (deg.)90.00, 95.11, 90.00
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-U70 / [(1~{S},6~{R},7~{S})-3-[3-[2,3-bis(chloranyl)phenyl]-2~{H}-pyrazolo[3,4-b]pyrazin-6-yl]-7-(4-methyl-1,3-thiazol-2-yl)-3-azabicyclo[4.1.0]heptan-7-yl]methanamine


Mass: 486.420 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H21Cl2N7S / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 242 / 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: 2.23 Å3/Da / Density % sol: 44.96 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, hanging drop / pH: 9
Details: 14.00 %w/v PEG 3350, 0.20 M NH4 Acetate, 0.10 M Tris pH=9.00

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X6A / Wavelength: 0.999987 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jun 24, 2020
RadiationMonochromator: M / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.999987 Å / Relative weight: 1
ReflectionResolution: 2.236→107.983 Å / Num. obs: 34069 / % possible obs: 90.3 % / Redundancy: 4.4 % / CC1/2: 0.996 / Net I/σ(I): 8.4
Reflection shellResolution: 2.236→2.485 Å / Num. unique obs: 1703 / CC1/2: 0.587

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Processing

Software
NameVersionClassification
REFMAC5.8.0155refinement
XDSdata reduction
pointlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.24→107.98 Å / Cor.coef. Fo:Fc: 0.929 / Cor.coef. Fo:Fc free: 0.879 / SU B: 22.26 / SU ML: 0.265 / Cross valid method: THROUGHOUT / ESU R: 1.43 / ESU R Free: 0.334 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.26379 857 2.5 %RANDOM
Rwork0.21589 ---
obs0.21707 33212 67.01 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 44.743 Å2
Baniso -1Baniso -2Baniso -3
1--2.31 Å20 Å2-0.68 Å2
2--3.12 Å20 Å2
3----0.67 Å2
Refinement stepCycle: 1 / Resolution: 2.24→107.98 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7857 0 64 242 8163
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0197934
X-RAY DIFFRACTIONr_bond_other_d0.0030.027356
X-RAY DIFFRACTIONr_angle_refined_deg1.5181.9510764
X-RAY DIFFRACTIONr_angle_other_deg1.228316821
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.3895969
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.13323.901382
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.05315.0681328
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.3931553
X-RAY DIFFRACTIONr_chiral_restr0.0790.21177
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.029052
X-RAY DIFFRACTIONr_gen_planes_other0.0020.021889
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.7882.2663900
X-RAY DIFFRACTIONr_mcbond_other1.7882.2663899
X-RAY DIFFRACTIONr_mcangle_it3.0543.7984861
X-RAY DIFFRACTIONr_mcangle_other3.0543.7994862
X-RAY DIFFRACTIONr_scbond_it1.8072.374034
X-RAY DIFFRACTIONr_scbond_other1.8072.3724035
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other2.9113.9375898
X-RAY DIFFRACTIONr_long_range_B_refined5.27319.3158240
X-RAY DIFFRACTIONr_long_range_B_other5.26219.288229
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Ens-ID: 1 / Number: 10950 / Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Rms dev position: 0.02 Å / Weight position: 0.05

Dom-IDAuth asym-ID
1A
2B
LS refinement shellResolution: 2.24→2.294 Å
RfactorNum. reflection% reflection
Rfree0.366 3 -
Rwork0.299 104 -
obs--2.88 %
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)
13.84093.7079-0.50855.175-0.18690.89280.0604-0.14480.00780.1953-0.08440.6722-0.1084-0.38420.02410.35740.060.07010.24510.02630.47516.507-24.84846.135
25.0121.2746-1.37075.0122-1.2673.1248-0.09660.2342-0.0849-0.27750.1830.07910.050.0502-0.08650.4426-0.0061-0.00850.1188-0.070.252119.397-39.21821.824
31.570.85730.52682.5380.79792.4655-0.04860.0664-0.0103-0.09030.07980.1208-0.04850.0031-0.03130.24590.01280.06490.0067-0.00780.186628.888-6.04440.801
43.5812.19190.71094.28780.63261.81350.051-0.2280.03790.2452-0.0422-0.49920.03810.2004-0.00890.30110.0409-0.0150.07440.00140.405531.93142.27324.175
54.01090.87941.33474.12290.22423.9463-0.01750.29080.0296-0.31790.1303-0.23410.00980.0186-0.11270.47040.01130.09340.14930.07490.309624.02856.359-1.731
61.99821.2287-0.59262.8886-0.59382.1076-0.05610.07370.0114-0.09330.0718-0.16780.07640.0305-0.01560.2610.0196-0.03040.00660.00130.175910.99323.09715.846
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A3 - 108
2X-RAY DIFFRACTION2A109 - 217
3X-RAY DIFFRACTION3A218 - 601
4X-RAY DIFFRACTION4B4 - 108
5X-RAY DIFFRACTION5B109 - 217
6X-RAY DIFFRACTION6B218 - 601

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