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- PDB-8s0i: A fragment-based inhibitor of SHP2 -

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Basic information

Entry
Database: PDB / ID: 8s0i
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 / 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 / regulation of protein export from nucleus / positive regulation of ossification / hormone metabolic process / Interleukin-37 signaling / Signaling by Leptin / MET activates PTPN11 / negative regulation of chondrocyte differentiation / Regulation of RUNX1 Expression and Activity / face morphogenesis / Costimulation by the CD28 family / ERBB signaling pathway / Signal regulatory protein family interactions / platelet formation / megakaryocyte development / triglyceride metabolic process / organ growth / negative regulation of type I interferon production / peptide hormone receptor binding / CTLA4 inhibitory signaling / Platelet sensitization by LDL / Interleukin-20 family signaling / PI-3K cascade:FGFR3 / Interleukin-6 signaling / PI-3K cascade:FGFR2 / STAT5 activation downstream of FLT3 ITD mutants / PI-3K cascade:FGFR4 / PI-3K cascade:FGFR1 / Prolactin receptor signaling / MAPK3 (ERK1) activation / regulation of cell adhesion mediated by integrin / PECAM1 interactions / regulation of type I interferon-mediated signaling pathway / MAPK1 (ERK2) activation / 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 / RET signaling / peptidyl-tyrosine dephosphorylation / Interleukin-3, Interleukin-5 and GM-CSF signaling / Regulation of IFNA/IFNB signaling / PI3K Cascade / PD-1 signaling / 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 / 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 / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / GPVI-mediated activation cascade / homeostasis of number of cells within a tissue / Tie2 Signaling / FRS-mediated FGFR1 signaling / cell adhesion molecule binding / T cell costimulation / cellular response to epidermal growth factor stimulus / FLT3 Signaling / protein dephosphorylation / positive regulation of interferon-beta production / hormone-mediated signaling pathway / phosphotyrosine residue binding / Downstream signal transduction / positive regulation of mitotic cell cycle / protein-tyrosine-phosphatase / axonogenesis / protein tyrosine kinase binding / 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 FGFR3 signaling / Negative regulation of FGFR2 signaling / insulin receptor binding / Negative regulation of FGFR4 signaling / Negative regulation of FGFR1 signaling / Spry regulation of FGF signaling / epidermal growth factor receptor signaling pathway / Signaling by SCF-KIT
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: 1.929 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)124,1884
Polymers123,8002
Non-polymers3882
Water7,963442
1
A: Tyrosine-protein phosphatase non-receptor type 11
hetero molecules


  • defined by author
  • Evidence: gel filtration
  • 62.1 kDa, 1 polymers
Theoretical massNumber of molelcules
Total (without water)62,0942
Polymers61,9001
Non-polymers1941
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Tyrosine-protein phosphatase non-receptor type 11
hetero molecules


  • defined by author
  • 62.1 kDa, 1 polymers
Theoretical massNumber of molelcules
Total (without water)62,0942
Polymers61,9001
Non-polymers1941
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)45.902, 212.545, 55.811
Angle α, β, γ (deg.)90.00, 96.79, 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-A1H4P / 3-phenyl-1H-pyrrolo[3,2-b]pyridine


Mass: 194.232 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C13H10N2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 442 / 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: 2.18 Å3/Da / Density % sol: 43.67 %
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: ESRF / Beamline: ID29 / Wavelength: 0.96862 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Apr 21, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.96862 Å / Relative weight: 1
ReflectionResolution: 1.929→45.58 Å / Num. obs: 77010 / % possible obs: 96.6 % / Redundancy: 3.4 % / Rrim(I) all: 0.047 / Net I/σ(I): 11.8
Reflection shellResolution: 1.929→1.97 Å / Mean I/σ(I) obs: 2 / Num. unique obs: 4165 / Rrim(I) all: 0.726 / % possible all: 89.4

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Processing

Software
NameClassification
XDSdata reduction
Aimlessdata scaling
CSearchphasing
REFMACrefinement
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.929→45.58 Å / Cor.coef. Fo:Fc: 0.95 / Cor.coef. Fo:Fc free: 0.943 / SU R Cruickshank DPI: 0.34 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.166 / SU Rfree Blow DPI: 0.143 / SU Rfree Cruickshank DPI: 0.145
Details: HYDROGENS WERE FULLY REFINED WITH FULL OCCUPANCY AT NUCLEAR POSITION.
RfactorNum. reflection% reflectionSelection details
Rfree0.2236 3896 5.06 %RANDOM
Rwork0.1934 ---
obs0.195 76996 97 %-
Displacement parametersBiso mean: 52.528 Å2
Baniso -1Baniso -2Baniso -3
1--2.9924 Å20 Å26.1506 Å2
2--2.2428 Å20 Å2
3---0.7497 Å2
Refine analyzeLuzzati coordinate error obs: 0.23 Å
Refinement stepCycle: LAST / Resolution: 1.929→45.58 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8130 0 30 442 8602
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.01316346HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.129459HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d3619SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes2702HARMONIC16
X-RAY DIFFRACTIONt_it16346HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion6.47
X-RAY DIFFRACTIONt_other_torsion16.34
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion1040SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact12581SEMIHARMONIC4
LS refinement shellResolution: 1.93→1.94 Å / Total num. of bins used: 51
RfactorNum. reflection% reflection
Rfree0.2986 -5.06 %
Rwork0.3049 1462 -
all0.3046 1540 -
obs--85.01 %
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)
10.5479-0.3103-0.07910.9142-0.0541-0.0266-0.0018-0.05090.00470.08920.07270.2143-0.00570.1627-0.0709-0.04640.00670.0271-0.0507-0.03090.10061.50291.190713.15
20.39540.1723-0.08030.92530.1394-0.0247-0.1342-0.03410.0383-0.12190.07870.20970.03620.13360.05550.0405-0.0052-0.0159-0.0871-0.01520.04332.194158.02559.9467
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|3 - A|528 }
2X-RAY DIFFRACTION2{ B|3 - B|528 }

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