[English] 日本語
Yorodumi
- PDB-8t6d: Identification of GDC-1971 (RLY-1971), a SHP2 inhibitor designed ... -

+
Open data


ID or keywords:

Loading...

-
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 / 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 / cerebellar cortex formation / negative regulation of neutrophil activation / positive regulation of hormone secretion / regulation of protein export from nucleus / positive regulation of ossification / positive regulation of lipopolysaccharide-mediated signaling pathway / Interleukin-37 signaling / Signaling by Leptin / hormone metabolic process / MET activates PTPN11 / Regulation of RUNX1 Expression and Activity / negative regulation of chondrocyte differentiation / face morphogenesis / Signal regulatory protein family interactions / ERBB signaling pathway / platelet formation / Interleukin-20 family signaling / Interleukin-6 signaling / triglyceride metabolic process / organ growth / megakaryocyte development / peptide hormone receptor binding / negative regulation of type I interferon production / PI-3K cascade:FGFR3 / Co-inhibition by CTLA4 / MAPK3 (ERK1) activation / Platelet sensitization by LDL / STAT5 activation downstream of FLT3 ITD mutants / PI-3K cascade:FGFR2 / PI-3K cascade:FGFR4 / PI-3K cascade:FGFR1 / MAPK1 (ERK2) activation / Prolactin receptor signaling / regulation of cell adhesion mediated by integrin / regulation of type I interferon-mediated signaling pathway / PECAM1 interactions / inner ear development / neurotrophin TRK receptor signaling pathway / Bergmann glial cell differentiation / Regulation of IFNA/IFNB signaling / positive regulation of intracellular signal transduction / peptidyl-tyrosine dephosphorylation / platelet-derived growth factor receptor signaling pathway / phosphoprotein phosphatase activity / RET signaling / Interleukin-3, Interleukin-5 and GM-CSF signaling / PI3K Cascade / ephrin receptor signaling pathway / Co-inhibition by PD-1 / fibroblast growth factor receptor signaling pathway / GAB1 signalosome / regulation of protein-containing complex assembly / Activated NTRK2 signals through FRS2 and FRS3 / positive regulation of insulin receptor signaling pathway / Regulation of IFNG signaling / negative regulation of insulin secretion / Signaling by CSF3 (G-CSF) / FRS-mediated FGFR3 signaling / Signaling by FLT3 ITD and TKD mutants / GPVI-mediated activation cascade / cell adhesion molecule binding / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / Tie2 Signaling / FRS-mediated FGFR1 signaling / homeostasis of number of cells within a tissue / hormone-mediated signaling pathway / negative regulation of T cell proliferation / T cell costimulation / FLT3 Signaling / phosphotyrosine residue binding / protein tyrosine phosphatase activity / protein-tyrosine-phosphatase / protein tyrosine phosphatase activity, metal-dependent / histone H2AXY142 phosphatase activity / non-membrane spanning protein tyrosine phosphatase activity / Downstream signal transduction / positive regulation of mitotic cell cycle / cellular response to epidermal growth factor stimulus / axonogenesis / positive regulation of interferon-beta production / protein tyrosine kinase binding / DNA damage checkpoint signaling / Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE) / integrin-mediated signaling pathway / positive regulation of D-glucose import / Negative regulation of FGFR3 signaling / insulin receptor binding / Negative regulation of FGFR2 signaling / Negative regulation of FGFR4 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 ...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

-
Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

-
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

-
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


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


Mass: 18.015 Da / Num. of mol.: 259 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

-
Experimental details

-
Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

-
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

-
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

-
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

+
About Yorodumi

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi

Thousand views of thousand structures

  • Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
  • This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
  • The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.

Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi

Read more