[English] 日本語
Yorodumi
- PDB-8cbh: SHP2 in complex with a novel allosteric inhibitor -

+
Open data


ID or keywords:

Loading...

-
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 / 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 / negative regulation of chondrocyte differentiation / Signaling by Leptin / 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 / triglyceride metabolic process / platelet formation / negative regulation of type I interferon production / megakaryocyte development / organ growth / CTLA4 inhibitory signaling / 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 / phosphoprotein phosphatase activity / inner ear development / MAPK1 (ERK2) activation / PECAM1 interactions / Bergmann glial cell differentiation / regulation of cell adhesion mediated by integrin / neurotrophin TRK receptor signaling pathway / regulation of type I interferon-mediated 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 / PI3K Cascade / Regulation of IFNA/IFNB signaling / PD-1 signaling / negative regulation of insulin secretion / ephrin receptor signaling pathway / regulation of protein-containing complex assembly / fibroblast growth factor receptor signaling pathway / GAB1 signalosome / Activated NTRK2 signals through FRS2 and FRS3 / Regulation of IFNG signaling / positive regulation of insulin receptor signaling pathway / homeostasis of number of cells within a tissue / FRS-mediated FGFR3 signaling / Signaling by CSF3 (G-CSF) / Signaling by FLT3 ITD and TKD mutants / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / cellular response to epidermal growth factor stimulus / FRS-mediated FGFR1 signaling / GPVI-mediated activation cascade / Tie2 Signaling / protein tyrosine kinase binding / T cell costimulation / FLT3 Signaling / positive regulation of interferon-beta production / hormone-mediated signaling pathway / cell adhesion molecule binding / phosphotyrosine residue binding / positive regulation of mitotic cell cycle / axonogenesis / Downstream signal transduction / protein dephosphorylation / Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE) / protein-tyrosine-phosphatase / DNA damage checkpoint signaling / protein tyrosine phosphatase activity / integrin-mediated signaling pathway / Negative regulation of FGFR3 signaling / Negative regulation of FGFR2 signaling / positive regulation of glucose import / Negative regulation of FGFR4 signaling / Negative regulation of FGFR1 signaling / brain development / Spry regulation of FGF signaling / multicellular organism growth / insulin receptor binding
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-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

-
Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

-
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

-
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 / Water


Mass: 18.015 Da / Num. of mol.: 242 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

-
Experimental details

-
Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

-
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

-
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

-
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

+
About Yorodumi

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi

Thousand views of thousand structures

  • Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
  • This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
  • The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.

Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi

Read more