6ZL5

CRYSTAL STRUCTURE OF KRAS-G12D(C118S) IN COMPLEX WITH BI-2852 AND GDP

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.65 Å
  • R-Value Free: 0.209 
  • R-Value Work: 0.196 
  • R-Value Observed: 0.197 

Starting Model: experimental
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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history. 


Literature

Drugging all RAS isoforms with one pocket.

Kessler, D., Bergner, A., Bottcher, J., Fischer, G., Dobel, S., Hinkel, M., Mullauer, B., Weiss-Puxbaum, A., McConnell, D.B.

(2020) Future Med Chem 12: 1911-1923

  • DOI: https://doi.org/10.4155/fmc-2020-0221
  • Primary Citation of Related Structures:  
    6ZIO, 6ZIR, 6ZIZ, 6ZJ0, 6ZL3, 6ZL5, 6ZLI

  • PubMed Abstract: 

    Activating mutations in the three human RAS genes, KRAS , NRAS and HRAS , are among the most common oncogenic drivers in human cancers. Covalent KRAS G12C inhibitors, which bind to the switch II pocket in the 'off state' of KRAS, represent the first direct KRAS drugs that entered human clinical trials. However, the remaining 85% of non-KRAS G12C -driven cancers remain undrugged as do NRAS and HRAS and no drugs targeting the 'on state' have been discovered so far. The switch I/II pocket is a second pocket for which the nanomolar inhibitor BI-2852 has been discovered. Here, we elucidate inhibitor binding modes in KRAS, NRAS and HRAS on and off and discuss future strategies to drug all RAS isoforms with this one pocket.

    • Organizational Affiliation: 

    Discovery Research, Boehringer Ingelheim Regional Center Vienna GmbH & Co. KG, 1121 Vienna, Austria.


Macromolecules
Find similar proteins by: 
(by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
GTPase KRas170Homo sapiensMutation(s): 2 
Gene Names: KRAS, KRAS2, RASK2
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
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  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
F0K (Subject of Investigation/LOI)
Query on F0K
Download Ideal Coordinates CCD File 
D [auth A](3~{S})-3-[2-[[[1-[(1-methylimidazol-4-yl)methyl]indol-6-yl]methylamino]methyl]-1~{H}-indol-3-yl]-5-oxidanyl-2,3-dihydroisoindol-1-one
C31 H28 N6 O2
JYEQLXOWWLNVDX-PMERELPUSA-N
GDP
Query on GDP
Download Ideal Coordinates CCD File 
C [auth A]GUANOSINE-5'-DIPHOSPHATE
C10 H15 N5 O11 P2
QGWNDRXFNXRZMB-UUOKFMHZSA-N
SO4
Query on SO4
Download Ideal Coordinates CCD File 
E [auth A]SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
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: 1.65 Å
  • R-Value Free: 0.209 
  • R-Value Work: 0.196 
  • R-Value Observed: 0.197 
  • Space Group: P 41 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 83.802α = 90
b = 83.802β = 90
c = 87.416γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
autoPROCdata reduction
XDSdata reduction
autoPROCdata scaling
Aimlessdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2020-08-19
    Type: Initial release
  • Version 1.1: 2020-11-25
    Changes: Database references
  • Version 1.2: 2024-01-31
    Changes: Data collection, Database references, Refinement description