4Q02: Second-site Screening Of K-ras In The Presence Of Covalently Attached First-site Ligands

K-Ras is a well-validated cancer target but is considered to be "undruggable" due to the lack of suitable binding pockets. We previously discovered small molecules that bind weakly to K-Ras but wanted to improve their binding affinities by identifying ligands that bind near our initial hits that we could link together. Here we describe an approach for identifying second site ligands that uses a cysteine residue to covalently attach a compound for tight binding to the first site pocket followed by a fragment screen for binding to a second site. This approach could be very useful for targeting Ras and other challenging drug targets.
PDB ID: 4Q02Download
MMDB ID: 123047
PDB Deposition Date: 2014/3/31
Updated in MMDB: 2014/09
Experimental Method:
x-ray diffraction
Resolution: 1.7  Å
Source Organism:
Similar Structures:
Biological Unit for 4Q02: monomeric; determined by author and by software (PISA)
Molecular Components in 4Q02
Label Count Molecule
Protein (1 molecule)
Gtpase Kras(Gene symbol: KRAS)
Molecule annotation
Chemicals (3 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB