6B0Y

Crystal Structure of small molecule ARS-917 covalently bound to K-Ras G12C


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.43 Å
  • R-Value Free: 0.207 
  • R-Value Work: 0.174 
  • R-Value Observed: 0.175 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

The reactivity-driven biochemical mechanism of covalent KRASG12Cinhibitors.

Hansen, R.Peters, U.Babbar, A.Chen, Y.Feng, J.Janes, M.R.Li, L.S.Ren, P.Liu, Y.Zarrinkar, P.P.

(2018) Nat Struct Mol Biol 25: 454-462

  • DOI: https://doi.org/10.1038/s41594-018-0061-5
  • Primary Citation of Related Structures:  
    6B0V, 6B0Y

  • PubMed Abstract: 

    Activating mutations in KRAS are among the most common tumor driver mutations. Until recently, KRAS had been considered undruggable with small molecules; the discovery of the covalent KRAS G12C inhibitors ARS-853 and ARS-1620 has demonstrated that it is feasible to inhibit KRAS with high potency in cells and animals. Although the biological activity of these inhibitors has been described, the biochemical mechanism of how the compounds achieve potent inhibition remained incompletely understood. We now show that the activity of ARS-853 and ARS-1620 is primarily driven by KRAS-mediated catalysis of the chemical reaction with Cys12 in human KRAS G12C , while the reversible binding affinity is weak, in the hundreds of micromolar or higher range. The mechanism resolves how an induced, shallow and dynamic pocket not expected to support high-affinity binding of small molecules can nevertheless be targeted with potent inhibitors and may be applicable to other targets conventionally considered undruggable.


  • Organizational Affiliation

    Wellspring Biosciences, Inc., San Diego, CA, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
GTPase KRas
A, B
170Homo sapiensMutation(s): 4 
Gene Names: KRASKRAS2RASK2
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 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
GDP
Query on GDP

Download Ideal Coordinates CCD File 
G [auth A],
M [auth B]
GUANOSINE-5'-DIPHOSPHATE
C10 H15 N5 O11 P2
QGWNDRXFNXRZMB-UUOKFMHZSA-N
8ZG
Query on 8ZG

Download Ideal Coordinates CCD File 
E [auth A],
K [auth B]
1-{4-[6-chloro-7-(2-fluorophenyl)quinazolin-4-yl]piperazin-1-yl}propan-1-one
C21 H20 Cl F N4 O
JPFKOCMCIFOGHK-UHFFFAOYSA-N
GOL
Query on GOL

Download Ideal Coordinates CCD File 
F [auth A],
H [auth B],
L [auth B]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
CA
Query on CA

Download Ideal Coordinates CCD File 
C [auth A],
D [auth A],
I [auth B],
J [auth B]
CALCIUM ION
Ca
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.43 Å
  • R-Value Free: 0.207 
  • R-Value Work: 0.174 
  • R-Value Observed: 0.175 
  • Space Group: P 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 33.43α = 77.45
b = 39.66β = 81.71
c = 61.85γ = 77.12
Software Package:
Software NamePurpose
iMOSFLMdata collection
SCALAdata scaling
PHASERphasing
REFMACrefinement
PDB_EXTRACTdata extraction
iMOSFLMdata reduction

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2018-05-16
    Type: Initial release
  • Version 1.1: 2018-05-30
    Changes: Data collection, Database references
  • Version 1.2: 2018-11-07
    Changes: Data collection, Database references
  • Version 1.3: 2023-10-04
    Changes: Data collection, Database references, Derived calculations, Refinement description