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- PDB-8s0k: A fragment-based inhibitor of SHP2 -

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Basic information

Entry
Database: PDB / ID: 8s0k
TitleA fragment-based inhibitor of SHP2
ComponentsTyrosine-protein phosphatase non-receptor type 11
KeywordsSIGNALING PROTEIN / protein tyrosine phophatase / SH2 domain / autoinhibition / allostery
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
: / Tyrosine-protein phosphatase non-receptor type 11
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.84 Å
AuthorsCleasby, A. / Price, A.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2024
Title: Fragment-Based Discovery of Allosteric Inhibitors of SH2 Domain-Containing Protein Tyrosine Phosphatase-2 (SHP2).
Authors: Day, J.E.H. / Berdini, V. / Castro, J. / Chessari, G. / Davies, T.G. / Day, P.J. / St Denis, J.D. / Fujiwara, H. / Fukaya, S. / Hamlett, C.C.F. / Hearn, K. / Hiscock, S.D. / Holvey, R.S. / ...Authors: Day, J.E.H. / Berdini, V. / Castro, J. / Chessari, G. / Davies, T.G. / Day, P.J. / St Denis, J.D. / Fujiwara, H. / Fukaya, S. / Hamlett, C.C.F. / Hearn, K. / Hiscock, S.D. / Holvey, R.S. / Ito, S. / Kandola, N. / Kodama, Y. / Liebeschuetz, J.W. / Martins, V. / Matsuo, K. / Mortenson, P.N. / Muench, S. / Nakatsuru, Y. / Ochiiwa, H. / Palmer, N. / Peakman, T. / Price, A. / Reader, M. / Rees, D.C. / Rich, S.J. / Shah, A. / Shibata, Y. / Smyth, T. / Twigg, D.G. / Wallis, N.G. / Williams, G. / Wilsher, N.E. / Woodhead, A. / Shimamura, T. / Johnson, C.N.
History
DepositionFeb 14, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 20, 2024Provider: repository / Type: Initial release
Revision 1.1Apr 10, 2024Group: 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

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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)124,5504
Polymers123,8002
Non-polymers7512
Water13,349741
1
A: Tyrosine-protein phosphatase non-receptor type 11
hetero molecules


  • defined by author
  • Evidence: gel filtration
  • 62.3 kDa, 1 polymers
Theoretical massNumber of molelcules
Total (without water)62,2752
Polymers61,9001
Non-polymers3751
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Tyrosine-protein phosphatase non-receptor type 11
hetero molecules


  • defined by author
  • 62.3 kDa, 1 polymers
Theoretical massNumber of molelcules
Total (without water)62,2752
Polymers61,9001
Non-polymers3751
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)46.068, 212.580, 55.926
Angle α, β, γ (deg.)90.00, 97.12, 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: 61899.789 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 BL21(DE3) (bacteria) / References: UniProt: Q06124, protein-tyrosine-phosphatase
#2: Chemical ChemComp-A1H4S / 3-[2,3-bis(chloranyl)phenyl]-5-methyl-6-(piperazin-1-ylmethyl)-1H-pyrrolo[3,2-b]pyridine


Mass: 375.295 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C19H20Cl2N4 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 741 / 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: 2.19 Å3/Da / Density % sol: 43.96 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8
Details: 0.5M K formate 15% PEG 3350 0.1M pH=8 Bis-Tris propane/HCl

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.97625 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Sep 15, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97625 Å / Relative weight: 1
ReflectionResolution: 1.84→106.29 Å / Num. obs: 90635 / % possible obs: 98.2 % / Redundancy: 3.1 % / Rrim(I) all: 0.048 / Net I/σ(I): 9.3
Reflection shellResolution: 1.84→1.87 Å / Mean I/σ(I) obs: 2.4 / Num. unique obs: 3288 / Rrim(I) all: 0.347 / % possible all: 87

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Processing

Software
NameClassification
XDSdata reduction
Aimlessdata scaling
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.84→106.29 Å / Cor.coef. Fo:Fc: 0.965 / Cor.coef. Fo:Fc free: 0.944 / SU B: 7.816 / SU ML: 0.117 / Cross valid method: THROUGHOUT / ESU R: 0.145 / ESU R Free: 0.139 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.22788 4552 5 %RANDOM
Rwork0.18131 ---
obs0.18368 85831 97.99 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 41.139 Å2
Baniso -1Baniso -2Baniso -3
1-1.32 Å20 Å2-1.01 Å2
2---0.34 Å2-0 Å2
3----0.7 Å2
Refinement stepCycle: 1 / Resolution: 1.84→106.29 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8146 0 50 741 8937
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0158397
X-RAY DIFFRACTIONr_bond_other_d0.0010.0177416
X-RAY DIFFRACTIONr_angle_refined_deg1.3231.75111336
X-RAY DIFFRACTIONr_angle_other_deg0.4731.72817447
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.50951008
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.69320.557413
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.76215.0221360
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.3481566
X-RAY DIFFRACTIONr_chiral_restr0.0620.21048
X-RAY DIFFRACTIONr_gen_planes_refined00.029440
X-RAY DIFFRACTIONr_gen_planes_other00.021538
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_it2.5284.6494035
X-RAY DIFFRACTIONr_mcbond_other2.5284.6514036
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it3.3295.5584362
X-RAY DIFFRACTIONr_scbond_other3.3245.5584360
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined6.84825.8069000
X-RAY DIFFRACTIONr_long_range_B_other6.80725.5678939
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.84→1.886 Å
RfactorNum. reflection% reflection
Rfree0.342 287 -
Rwork0.336 5601 -
obs--86.83 %
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)
11.7629-1.2384-0.37013.11130.13540.769-0.0323-0.12950.17640.22390.12710.3011-0.17250.0243-0.09480.06070.0050.04340.0109-0.00620.11.50051.24613.4158
21.43781.04980.20752.64520.36640.7933-0.11610.098-0.1246-0.19680.11140.210.1564-0.01370.00470.0901-0.0078-0.00130.01310.00210.06262.155658.10089.3082
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A3 - 528
2X-RAY DIFFRACTION2B3 - 530

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