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

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Basic information

Entry
Database: PDB / ID: 8rzw
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 / 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 / negative regulation of neutrophil activation / cerebellar cortex formation / positive regulation of hormone secretion / regulation of protein export from nucleus / Interleukin-37 signaling / positive regulation of lipopolysaccharide-mediated signaling pathway / positive regulation of ossification / Signaling by Leptin / MET activates PTPN11 / hormone metabolic process / Regulation of RUNX1 Expression and Activity / negative regulation of chondrocyte differentiation / Signal regulatory protein family interactions / face morphogenesis / ERBB signaling pathway / platelet formation / triglyceride metabolic process / megakaryocyte development / negative regulation of type I interferon production / organ growth / Interleukin-20 family signaling / Interleukin-6 signaling / PI-3K cascade:FGFR3 / Co-inhibition by CTLA4 / Platelet sensitization by LDL / STAT5 activation downstream of FLT3 ITD mutants / peptide hormone receptor binding / PI-3K cascade:FGFR2 / PI-3K cascade:FGFR4 / MAPK3 (ERK1) activation / PI-3K cascade:FGFR1 / Prolactin receptor signaling / neurotrophin TRK receptor signaling pathway / regulation of cell adhesion mediated by integrin / regulation of type I interferon-mediated signaling pathway / MAPK1 (ERK2) activation / platelet-derived growth factor receptor signaling pathway / PECAM1 interactions / inner ear development / Bergmann glial cell differentiation / peptidyl-tyrosine dephosphorylation / non-membrane spanning protein tyrosine phosphatase activity / positive regulation of intracellular signal transduction / phosphoprotein phosphatase activity / Regulation of IFNA/IFNB signaling / RET signaling / Interleukin-3, Interleukin-5 and GM-CSF signaling / PI3K Cascade / Co-inhibition by PD-1 / fibroblast growth factor receptor signaling pathway / positive regulation of insulin receptor signaling pathway / GAB1 signalosome / ephrin receptor signaling pathway / regulation of protein-containing complex assembly / Regulation of IFNG signaling / Activated NTRK2 signals through FRS2 and FRS3 / GPVI-mediated activation cascade / Signaling by CSF3 (G-CSF) / FRS-mediated FGFR3 signaling / cell adhesion molecule binding / Signaling by FLT3 ITD and TKD mutants / negative regulation of T cell proliferation / T cell costimulation / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / hormone-mediated signaling pathway / FRS-mediated FGFR1 signaling / Tie2 Signaling / phosphotyrosine residue binding / protein-tyrosine-phosphatase / FLT3 Signaling / homeostasis of number of cells within a tissue / Downstream signal transduction / positive regulation of mitotic cell cycle / axonogenesis / protein tyrosine phosphatase activity / positive regulation of interferon-beta production / protein tyrosine kinase binding / cellular response to epidermal growth factor stimulus / DNA damage checkpoint signaling / Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE) / integrin-mediated signaling pathway / positive regulation of D-glucose import / insulin receptor binding / Negative regulation of FGFR3 signaling / Negative regulation of FGFR2 signaling / Negative regulation of FGFR4 signaling / Negative regulation of FGFR1 signaling / cellular response to mechanical stimulus / Spry regulation of FGF signaling
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 profile. ...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 profile. / Tyrosine-specific protein phosphatases domain / 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: 2.02 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 13, 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)124,1284
Polymers123,8002
Non-polymers3282
Water9,044502
1
A: Tyrosine-protein phosphatase non-receptor type 11
hetero molecules


Theoretical massNumber of molelcules
Total (without water)62,0642
Polymers61,9001
Non-polymers1641
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)62,0642
Polymers61,9001
Non-polymers1641
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)46.063, 212.634, 55.987
Angle α, β, γ (deg.)90.00, 97.16, 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-A1H4N / 3,5-bis(chloranyl)pyrazin-2-amine / HYDROXYETHYLAMINE BACE INHIBITOR


Mass: 163.993 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C4H3Cl2N3 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 502 / 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: 2.2 Å3/Da / Density % sol: 44.03 %
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: 0.97623 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Sep 10, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97623 Å / Relative weight: 1
ReflectionResolution: 2.02→49.24 Å / Num. obs: 68408 / % possible obs: 98.4 % / Redundancy: 3.4 % / Rrim(I) all: 0.079 / Net I/σ(I): 8
Reflection shellResolution: 2.02→2.07 Å / Num. unique obs: 4576 / Rrim(I) all: 0.78

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Processing

Software
NameClassification
XDSdata reduction
XDSdata reduction
Aimlessdata scaling
Aimlessdata scaling
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.02→49.28 Å / Cor.coef. Fo:Fc: 0.945 / Cor.coef. Fo:Fc free: 0.908 / SU B: 13.4 / SU ML: 0.185 / Cross valid method: THROUGHOUT / ESU R: 0.235 / ESU R Free: 0.204 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.27183 3486 5.1 %RANDOM
Rwork0.21556 ---
obs0.21842 65261 98.73 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 50.892 Å2
Baniso -1Baniso -2Baniso -3
1-2.73 Å20 Å2-0.19 Å2
2---4.43 Å2-0 Å2
3---1.7 Å2
Refinement stepCycle: 1 / Resolution: 2.02→49.28 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8076 0 18 502 8596
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0158259
X-RAY DIFFRACTIONr_bond_other_d0.0010.0177308
X-RAY DIFFRACTIONr_angle_refined_deg1.2651.75211134
X-RAY DIFFRACTIONr_angle_other_deg0.4571.72917180
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.6915988
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.43520.37405
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.909151331
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.8021566
X-RAY DIFFRACTIONr_chiral_restr0.0580.21033
X-RAY DIFFRACTIONr_gen_planes_refined00.029269
X-RAY DIFFRACTIONr_gen_planes_other00.021511
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_it2.0464.0193982
X-RAY DIFFRACTIONr_mcbond_other2.0454.023983
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it2.4784.6634277
X-RAY DIFFRACTIONr_scbond_other2.4744.664274
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined6.72522.2468761
X-RAY DIFFRACTIONr_long_range_B_other6.70822.018722
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.02→2.072 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.408 259 -
Rwork0.336 4889 -
obs--99.34 %
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)
11.4932-1.2566-0.29123.34790.11210.91-0.0061-0.13480.14010.29740.11310.3309-0.140.0311-0.1070.067-0.00560.02740.3592-0.03510.22981.56581.152313.0417
21.08260.81050.15952.72010.32830.7313-0.14260.0712-0.1495-0.25210.07420.26680.15350.00410.06840.1181-0.0065-0.05830.3867-0.01540.21082.289958.1229.954
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A3 - 528
2X-RAY DIFFRACTION2B3 - 528

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