Conformational Plasticity and Druggability of Membrane-Bound K-Ras

Abstract

Despite decades of studies and the well-established roles of human Ras proteins in health and disease, much remains to be learned about how they work at the molecular level. Major challenges associated with the highly dynamic nature of these proteins and the resolution limits of experimental techniques have hampered our ability to address a number of key issues. These include, at the fundamental level, the sources of signaling specificity and non-overlapping membrane organization of homologous Ras proteins, as well as the structural determinants for the distinct role of specific point mutations in different cancer types. At a more practical level, we lacked the means by which to challenge the “invincibility” of Ras as an anti-cancer drug target. Considerable progress has been made over the last several years toward addressing each of these issues. Molecular simulations and other computational structural biology techniques have made significant contributions to this progress. Our laboratory studies Ras proteins using multi-scale molecular dynamics simulations in solution and membrane environments coupled with a variety of novel concepts, analysis tools and collaborative experiments. The current presentation will focus on the clinically most relevant isoform of Ras proteins: K-Ras. We will discuss our recent efforts toward elucidating the mechanisms of membrane binding and oligomeration of K-Ras as well as the impact of selected point mutations on its dynamics. We will highlight how some of the lessons from Ras can be generalized to other lipid-modified signaling proteins.