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- PDB-8wx7: Crystal structure of SHP2 in complex with JAB-3186 -

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Basic information

Entry
Database: PDB / ID: 8wx7
TitleCrystal structure of SHP2 in complex with JAB-3186
ComponentsTyrosine-protein phosphatase non-receptor type 11
KeywordsHYDROLASE / phosphatase cancer
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 / PI-3K cascade:FGFR1 / MAPK3 (ERK1) activation / 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 / Bergmann glial cell differentiation / inner ear development / 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 / FRS-mediated FGFR3 signaling / Signaling by CSF3 (G-CSF) / cell adhesion molecule binding / negative regulation of T cell proliferation / T cell costimulation / Signaling by FLT3 ITD and TKD mutants / 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 / MOLECULAR REPLACEMENT / Resolution: 2.02 Å
AuthorsMa, C. / Gao, P. / Kang, D. / Han, H. / Sun, X. / Zhang, W. / Qian, D. / Wang, Y. / Long, W.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2024
Title: Discovery of JAB-3312, a Potent SHP2 Allosteric Inhibitor for Cancer Treatment.
Authors: Ma, C. / Kang, D. / Gao, P. / Zhang, W. / Wu, X. / Xu, Z. / Han, H. / Zhang, L. / Cai, Y. / Wang, Y. / Wang, Y. / Long, W.
History
DepositionOct 27, 2023Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Aug 14, 2024Provider: repository / Type: Initial release
Revision 1.1Sep 4, 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)123,19124
Polymers120,6102
Non-polymers2,58122
Water5,657314
1
A: Tyrosine-protein phosphatase non-receptor type 11
hetero molecules


Theoretical massNumber of molelcules
Total (without water)61,68712
Polymers60,3051
Non-polymers1,38211
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area230 Å2
ΔGint-17 kcal/mol
Surface area21330 Å2
MethodPISA
2
B: Tyrosine-protein phosphatase non-receptor type 11
hetero molecules


Theoretical massNumber of molelcules
Total (without water)61,50512
Polymers60,3051
Non-polymers1,20011
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area190 Å2
ΔGint-15 kcal/mol
Surface area22450 Å2
MethodPISA
Unit cell
Length a, b, c (Å)45.711, 211.121, 55.839
Angle α, β, γ (deg.)90.00, 95.83, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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Protein , 1 types, 2 molecules AB

#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

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Non-polymers , 5 types, 336 molecules

#2: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#3: Chemical ChemComp-XD8 / (5~{S})-1'-[6-azanyl-5-(2-azanyl-3-chloranyl-pyridin-4-yl)sulfanyl-pyrazin-2-yl]spiro[5,7-dihydrocyclopenta[b]pyridine-6,4'-piperidine]-5-amine


Mass: 454.979 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H23ClN8S / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 15 / Source method: obtained synthetically / Formula: SO4
#5: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Cl
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 314 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.22 Å3/Da / Density % sol: 44.65 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop
Details: 0.1 M HEPES pH 7.5, 0.2 M ammonium sulphate, 28 % w/v PEG3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NFPSS / Beamline: BL19U1 / Wavelength: 0.97893 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: May 17, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97893 Å / Relative weight: 1
ReflectionResolution: 2.02→50 Å / Num. obs: 68653 / % possible obs: 99.1 % / Redundancy: 3.1 % / CC1/2: 0.973 / Rmerge(I) obs: 0.097 / Net I/σ(I): 12.4
Reflection shellResolution: 2.02→2.09 Å / Rmerge(I) obs: 0.513 / Num. unique obs: 6645 / CC1/2: 0.717 / % possible all: 96.8

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Processing

Software
NameVersionClassification
REFMAC5.8.0258refinement
HKL-3000data scaling
HKL-3000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.02→49.21 Å / Cor.coef. Fo:Fc: 0.96 / Cor.coef. Fo:Fc free: 0.936 / SU B: 6.01 / SU ML: 0.159 / Cross valid method: THROUGHOUT / ESU R: 0.208 / ESU R Free: 0.182 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.24599 3417 5 %RANDOM
Rwork0.19463 ---
obs0.19729 64516 98.97 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 41.431 Å2
Baniso -1Baniso -2Baniso -3
1--0.01 Å20 Å20.01 Å2
2--0 Å20 Å2
3---0 Å2
Refinement stepCycle: 1 / Resolution: 2.02→49.21 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms7868 0 148 314 8330
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0138184
X-RAY DIFFRACTIONr_bond_other_d0.0010.0177326
X-RAY DIFFRACTIONr_angle_refined_deg1.4741.65911091
X-RAY DIFFRACTIONr_angle_other_deg1.2711.58616954
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.1255991
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.23722.103447
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.523151365
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.7391557
X-RAY DIFFRACTIONr_chiral_restr0.0640.21043
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.029114
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021741
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_it3.2674.4043982
X-RAY DIFFRACTIONr_mcbond_other3.2654.4033981
X-RAY DIFFRACTIONr_mcangle_it4.586.5844958
X-RAY DIFFRACTIONr_mcangle_other4.5816.5854959
X-RAY DIFFRACTIONr_scbond_it3.6144.6624202
X-RAY DIFFRACTIONr_scbond_other3.5354.6154143
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other5.2576.8036041
X-RAY DIFFRACTIONr_long_range_B_refined7.249.468852
X-RAY DIFFRACTIONr_long_range_B_other7.17349.48818
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
Rfree0.34 252 -
Rwork0.313 4684 -
obs--95.6 %

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