5F2E

Crystal Structure of small molecule ARS-853 covalently bound to K-Ras G12C


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.40 Å
  • R-Value Free: 0.176 
  • R-Value Work: 0.150 
  • R-Value Observed: 0.152 

Starting Model: experimental
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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Selective Inhibition of Oncogenic KRAS Output with Small Molecules Targeting the Inactive State.

Patricelli, M.P.Janes, M.R.Li, L.S.Hansen, R.Peters, U.Kessler, L.V.Chen, Y.Kucharski, J.M.Feng, J.Ely, T.Chen, J.H.Firdaus, S.J.Babbar, A.Ren, P.Liu, Y.

(2016) Cancer Discov 6: 316-329

  • DOI: https://doi.org/10.1158/2159-8290.CD-15-1105
  • Primary Citation of Related Structures:  
    5F2E

  • PubMed Abstract: 

    KRAS gain-of-function mutations occur in approximately 30% of all human cancers. Despite more than 30 years of KRAS-focused research and development efforts, no targeted therapy has been discovered for cancers with KRAS mutations. Here, we describe ARS-853, a selective, covalent inhibitor of KRAS(G12C) that inhibits mutant KRAS-driven signaling by binding to the GDP-bound oncoprotein and preventing activation. Based on the rates of engagement and inhibition observed for ARS-853, along with a mutant-specific mass spectrometry-based assay for assessing KRAS activation status, we show that the nucleotide state of KRAS(G12C) is in a state of dynamic flux that can be modulated by upstream signaling factors. These studies provide convincing evidence that the KRAS(G12C) mutation generates a "hyperexcitable" rather than a "statically active" state and that targeting the inactive, GDP-bound form is a promising approach for generating novel anti-RAS therapeutics. A cell-active, mutant-specific, covalent inhibitor of KRAS(G12C) is described that targets the GDP-bound, inactive state and prevents subsequent activation. Using this novel compound, we demonstrate that KRAS(G12C) oncoprotein rapidly cycles bound nucleotide and responds to upstream signaling inputs to maintain a highly active state.


  • Organizational Affiliation

    Wellspring Biosciences, La Jolla, California.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
GTPase KRas170Homo sapiensMutation(s): 10 
Gene Names: KRASKRAS2RASK2
EC: 3.6.5.2
UniProt & NIH Common Fund Data Resources
Find proteins for P01116 (Homo sapiens)
Explore P01116 
Go to UniProtKB:  P01116
PHAROS:  P01116
GTEx:  ENSG00000133703 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP01116
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
GDP
Query on GDP

Download Ideal Coordinates CCD File 
G [auth A]GUANOSINE-5'-DIPHOSPHATE
C10 H15 N5 O11 P2
QGWNDRXFNXRZMB-UUOKFMHZSA-N
5UT
Query on 5UT

Download Ideal Coordinates CCD File 
E [auth A]1-[3-[4-[2-[[4-chloranyl-5-(1-methylcyclopropyl)-2-oxidanyl-phenyl]amino]ethanoyl]piperazin-1-yl]azetidin-1-yl]prop-2-en-1-one
C22 H29 Cl N4 O3
IPFOCHMOYUMURK-UHFFFAOYSA-N
GOL
Query on GOL

Download Ideal Coordinates CCD File 
C [auth A],
D [auth A]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
GLY
Query on GLY

Download Ideal Coordinates CCD File 
F [auth A]GLYCINE
C2 H5 N O2
DHMQDGOQFOQNFH-UHFFFAOYSA-N
MG
Query on MG

Download Ideal Coordinates CCD File 
B [auth A]MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.40 Å
  • R-Value Free: 0.176 
  • R-Value Work: 0.150 
  • R-Value Observed: 0.152 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 39.11α = 90
b = 43.08β = 90
c = 93.96γ = 90
Software Package:
Software NamePurpose
iMOSFLMdata reduction
SCALAdata scaling
PHASERphasing
REFMACrefinement
PDB_EXTRACTdata extraction

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2016-01-13
    Type: Initial release
  • Version 1.1: 2016-03-16
    Changes: Database references
  • Version 1.2: 2017-11-22
    Changes: Derived calculations, Refinement description
  • Version 1.3: 2023-09-27
    Changes: Data collection, Database references, Derived calculations, Refinement description