4Q01

Second-site screening of K-Ras in the presence of covalently attached first-site ligands

Summary for 4Q01

• Entry DOI: 10.2210/pdb4q01/pdb
• Related: 4PZY 4PZZ 4Q02 4Q03
• Descriptor: K-Ras, GUANOSINE-5'-DIPHOSPHATE, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: small gtpase, signaling transduction, sos, raf, cytosol, hydrolase
• Biological source: Homo sapiens
• Cellular location: Cell membrane; Lipid-anchor; Cytoplasmic side: P01116
• Total number of polymer chains: 2
• Total formula weight: 39883.16

Authors

Sun, Q.,Phan, J.,Friberg, A.,Camper, D.V.,Olejniczak, E.T.,Fesik, S.W. (deposition date: 2014-03-31, release date: 2014-09-10)

Primary citation

Sun, Q.,Phan, J.,Friberg, A.R.,Camper, D.V.,Olejniczak, E.T.,Fesik, S.W.
A method for the second-site screening of K-Ras in the presence of a covalently attached first-site ligand.
J.Biomol.Nmr, 60:11-14, 2014

PubMed Abstract: 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.

PubMed: 25087006
DOI: 10.1007/s10858-014-9849-8

Experimental method

X-RAY DIFFRACTION (1.291 Å)