Ruth Nussinov’s algorithm for the prediction of RNA secondary structure is still the leading method. She proposed ‘Conformational Selection and Population Shift’ as an alternative to the textbook ‘Induced-Fit’ model in molecular recognition. Her recent studies unveiled the key role of allostery under normal conditions and in disease and the principles of allosteric drug discovery. She uncovered the structural basis for cancer signaling, and its mechanistic principles; predicted GTP-dependent K-Ras dimer structures and suggested that K-Ras4B dimerizes via two distinct interfaces and explained the consequences for Raf’s activation and MAPK signaling; elucidated calmodulin’s role in KRAS-driven adenocarcinomas; the critical role of oncogenic KRAS in the initiation of cancer through deregulation of the G1 cell cycle, and proposed a new view of Ras isoforms. This new view argues for multiple signaling states of palmitoylated Ras isoforms, such as K-Ras4A. This view questions the completeness and accuracy of small GTPase Ras isoform statistics in different cancer types and calls for reevaluation of concepts and protocols. Importantly, the multiple signaling states also call for reconsideration of oncogenic Ras therapeutics.
Ras signaling: a challenge to the biological sciences
Ras proteins are classical members of small GTPases that function as molecular switches by alternating between inactive GDP-bound and active GTP-bound states. Ras activation is regulated by guanine nucleotide exchange factors that catalyze the exchange of GDP by GTP, and inactivation is terminated by GTPase-activating proteins that accelerate the intrinsic GTP hydrolysis rate by orders of magnitude. Ras has multiple partners, signals through several key pathways and fulfills critical functions in the cell life. Mutations in Ras are common in a variety of cancers; yet it is still undruggable. Consequently, it is at the center of an NCI initiative. In my talk, I will provide the background on Ras and an overview of our recent work, highlighting how it may help in elucidating vital questions in Ras biology and hopefully contribute to therapeutic strategies.