Fig. 1.

Overview of the Ras activation cycle and design of a Sos-based proteomimetic. (A) The cellular activity of Ras is tightly controlled as part of a balanced feedback loop. Oncogenic mutations shift this balance and increase the cellular concentration of Ras-GTP leading to aberrant downstream signaling. The molecular model shows the complex between Ras (gray ribbon) and its guanine exchange factor Sos (green). Sos inserts a helical hairpin (pink and blue helices) into the nucleotide binding pocket of Ras to mediate nucleotide exchange. The Ras nucleotide binding pocket is highlighted in yellow. Segments of Sos are not shown to highlight interactions of the helical hairpin with Ras (PDB code: 1NVW). (B) The molecular models depict critical Sos helices and the design of a constrained Sos proteomimetic as a Ras inhibitor. GDP, guanosine 5′-diphosphate; GTP, guanosine 5′-triphosphate; GAP, GTPase activating protein; GEF, guanine nucleotide exchange factor.