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- PDB-8t6d: Identification of GDC-1971 (RLY-1971), a SHP2 inhibitor designed ... -

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Basic information

Entry
Database: PDB / ID: 8t6d
TitleIdentification of GDC-1971 (RLY-1971), a SHP2 inhibitor designed for the treatment of solid tumors
ComponentsTyrosine-protein phosphatase non-receptor type 11
KeywordsHYDROLASE / Phosphatase / Tumor target / inhibitor
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-YR2 / Tyrosine-protein phosphatase non-receptor type 11
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.4 Å
AuthorsTang, Y. / Nguyen, V. / Wilbur, J.D.
Funding support1items
OrganizationGrant numberCountry
Other private
CitationJournal: J.Med.Chem. / Year: 2023
Title: Identification of GDC-1971 (RLY-1971), a SHP2 Inhibitor Designed for the Treatment of Solid Tumors.
Authors: Taylor, A.M. / Williams, B.R. / Giordanetto, F. / Kelley, E.H. / Lescarbeau, A. / Shortsleeves, K. / Tang, Y. / Walters, W.P. / Arrazate, A. / Bowman, C. / Brophy, E. / Chan, E.W. / ...Authors: Taylor, A.M. / Williams, B.R. / Giordanetto, F. / Kelley, E.H. / Lescarbeau, A. / Shortsleeves, K. / Tang, Y. / Walters, W.P. / Arrazate, A. / Bowman, C. / Brophy, E. / Chan, E.W. / Deshmukh, G. / Greisman, J.B. / Hunsaker, T.L. / Kipp, D.R. / Saenz Lopez-Larrocha, P. / Maddalo, D. / Martin, I.J. / Maragakis, P. / Merchant, M. / Murcko, M. / Nisonoff, H. / Nguyen, V. / Nguyen, V. / Orozco, O. / Owen, C. / Pierce, L. / Schmidt, M. / Shaw, D.E. / Smith, S. / Therrien, E. / Tran, J.C. / Watters, J. / Waters, N.J. / Wilbur, J. / Willmore, L.
History
DepositionJun 15, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 11, 2023Provider: repository / Type: Initial release
Revision 1.1Oct 25, 2023Group: 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

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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)122,44413
Polymers120,6702
Non-polymers1,77411
Water4,666259
1
A: Tyrosine-protein phosphatase non-receptor type 11
hetero molecules


Theoretical massNumber of molelcules
Total (without water)61,2707
Polymers60,3351
Non-polymers9356
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)61,1746
Polymers60,3351
Non-polymers8395
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)47.020, 214.218, 56.044
Angle α, β, γ (deg.)90.000, 97.170, 90.000
Int Tables number4
Space group name H-MP1211
Space group name HallP2yb

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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 / Shp2 / SH-PTP3


Mass: 60335.035 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-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 9 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-YR2 / (3R)-1'-[3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-6-yl]-3H-spiro[[1]benzofuran-2,4'-piperidin]-3-amine


Mass: 454.527 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C25H26N8O / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 259 / 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: 2.32 Å3/Da / Density % sol: 47 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop
Details: 19% PEG 3350,100 mM Tris-HCl (pH 8.5), 300 mM Ammonium Sulfate

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Data collection

DiffractionMean temperature: 101 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 8.3.1 / Wavelength: 1.11584 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Aug 26, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.11584 Å / Relative weight: 1
ReflectionResolution: 2.4→49.35 Å / Num. obs: 42137 / % possible obs: 98.4 % / Redundancy: 6.7 % / Biso Wilson estimate: 36.48 Å2 / CC1/2: 0.995 / Rmerge(I) obs: 0.14 / Net I/σ(I): 8.9
Reflection shellResolution: 2.4→2.486 Å / Rmerge(I) obs: 0.85 / Num. unique obs: 4264 / CC1/2: 0.726 / % possible all: 100

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
XDSdata reduction
SCALEPACKdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.4→49.35 Å / SU ML: 0.3578 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 31.5189
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.296 2124 5.04 %
Rwork0.2387 39993 -
obs0.2416 42117 98.4 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 39.1 Å2
Refinement stepCycle: LAST / Resolution: 2.4→49.35 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8055 0 113 259 8427
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00128397
X-RAY DIFFRACTIONf_angle_d0.378311346
X-RAY DIFFRACTIONf_chiral_restr0.03871204
X-RAY DIFFRACTIONf_plane_restr0.00211457
X-RAY DIFFRACTIONf_dihedral_angle_d6.63641131
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.4-2.460.36051560.31042714X-RAY DIFFRACTION99.83
2.46-2.520.34351390.29872691X-RAY DIFFRACTION99.68
2.52-2.590.33691400.28712711X-RAY DIFFRACTION99.72
2.59-2.660.34811440.2742664X-RAY DIFFRACTION99.72
2.66-2.750.30291530.26642698X-RAY DIFFRACTION99.65
2.75-2.850.3121500.26352672X-RAY DIFFRACTION99.75
2.85-2.960.3571540.26092739X-RAY DIFFRACTION99.86
2.96-3.090.31111270.26092683X-RAY DIFFRACTION99.79
3.09-3.260.33211350.24052704X-RAY DIFFRACTION99.68
3.26-3.460.30961410.24472684X-RAY DIFFRACTION99.51
3.46-3.730.40131080.29652414X-RAY DIFFRACTION88.06
3.73-4.10.33731350.23332515X-RAY DIFFRACTION93.51
4.1-4.70.2241510.18432717X-RAY DIFFRACTION99.07
4.7-5.920.22011350.19592681X-RAY DIFFRACTION99.33
5.92-49.350.23761560.20392706X-RAY DIFFRACTION99

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