Generation of RAS-targeted therapeutics has long been considered a "holy grail" in cancer research. However, a lack of binding pockets on the surface of RAS and its picomolar affinity for guanine nucleotides have made isolation of inhibitors particularly challenging. We recently described a monobody, termed NS1, that blocks RAS signaling and oncogenic transformation. NS1 binds to the α4-β6-α5 interface of H-RAS and K-RAS thus preventing RAS dimerization and nanoclustering, which in turn prevents RAS-stimulated dimerization and activation of RAF. Interestingly, NS1 reduces interaction of oncogenic K-RAS, but not H-RAS, with RAF and reduces K-RAS plasma membrane localization. Here, we show that these isoform specific effects of NS1 on RAS:RAF are due to the distinct hypervariable regions of RAS isoforms. NS1 inhibited wild type RAS function by reducing RAS GTP levels. These findings reveal that NS1 disrupts RAS signaling through a mechanism that is more complex than simply inhibiting RAS dimerization and nanoclustering.

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6748372PMC
http://dx.doi.org/10.1080/21541248.2017.1333188DOI Listing

Publication Analysis

Top Keywords

ras
9
ras signaling
8
ras dimerization
8
dimerization nanoclustering
8
ns1
6
targeting α4-α5
4
α4-α5 interface
4
interface ras
4
ras multiple
4
multiple levels
4

Similar Publications

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!