6OIM

Crystal Structure of human KRAS G12C covalently bound to AMG 510


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.65 Å
  • R-Value Free: 0.215 
  • R-Value Work: 0.181 
  • R-Value Observed: 0.183 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity.

Canon, J.Rex, K.Saiki, A.Y.Mohr, C.Cooke, K.Bagal, D.Gaida, K.Holt, T.Knutson, C.G.Koppada, N.Lanman, B.A.Werner, J.Rapaport, A.S.San Miguel, T.Ortiz, R.Osgood, T.Sun, J.R.Zhu, X.McCarter, J.D.Volak, L.P.Houk, B.E.Fakih, M.G.O'Neil, B.H.Price, T.J.Falchook, G.S.Desai, J.Kuo, J.Govindan, R.Hong, D.S.Ouyang, W.Henary, H.Arvedson, T.Cee, V.J.Lipford, J.R.

(2019) Nature 575: 217-223

  • DOI: https://doi.org/10.1038/s41586-019-1694-1
  • Primary Citation of Related Structures:  
    6OIM

  • PubMed Abstract: 

    KRAS is the most frequently mutated oncogene in cancer and encodes a key signalling protein in tumours 1,2 . The KRAS(G12C) mutant has a cysteine residue that has been exploited to design covalent inhibitors that have promising preclinical activity 3-5 . Here we optimized a series of inhibitors, using novel binding interactions to markedly enhance their potency and selectivity. Our efforts have led to the discovery of AMG 510, which is, to our knowledge, the first KRAS(G12C) inhibitor in clinical development. In preclinical analyses, treatment with AMG 510 led to the regression of KRAS G12C tumours and improved the anti-tumour efficacy of chemotherapy and targeted agents. In immune-competent mice, treatment with AMG 510 resulted in a pro-inflammatory tumour microenvironment and produced durable cures alone as well as in combination with immune-checkpoint inhibitors. Cured mice rejected the growth of isogenic KRAS G12D tumours, which suggests adaptive immunity against shared antigens. Furthermore, in clinical trials, AMG 510 demonstrated anti-tumour activity in the first dosing cohorts and represents a potentially transformative therapy for patients for whom effective treatments are lacking.


  • Organizational Affiliation

    Amgen Research, Amgen Inc, Thousand Oaks, CA, USA. jcanon@amgen.com.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
GTPase KRas183Homo 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
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.65 Å
  • R-Value Free: 0.215 
  • R-Value Work: 0.181 
  • R-Value Observed: 0.183 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 40.868α = 90
b = 58.417β = 90
c = 65.884γ = 90
Software Package:
Software NamePurpose
BOSdata collection
HKL-2000data reduction
DENZOdata reduction
HKL-2000data scaling
SCALEPACKdata scaling
MOLREPphasing
REFMACrefinement
Cootmodel building

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2019-11-06 
  • Deposition Author(s): Mohr, C.

Revision History  (Full details and data files)

  • Version 1.0: 2019-11-06
    Type: Initial release
  • Version 1.1: 2019-11-13
    Changes: Data collection, Database references
  • Version 1.2: 2019-11-27
    Changes: Database references
  • Version 1.3: 2019-12-18
    Changes: Derived calculations, Structure summary