Ras GTPases are key players in cellular signalling because they act as binary switches. These states manifest through toggling between an active (
GTP-loaded) and an inactive (
GDP-loaded) form. The hydrolysis and replenishing of
GTP is controlled by two additional
protein classes: GAP (
GTPase-activating)- and GEF (
Guanine nucleotide exchange factors)-
proteins. The complex interplay of the
proteins is known as the
GTPase-cycle. Several point mutations of the
Ras protein deregulate this cycle. Mutations in Ras are associated with up to one-third of human
cancers. The three
isoforms of Ras (H, N, K) exhibit high sequence similarity and mainly differ in a region called HVR (hypervariable region). The HVR governs the differential action and cellular distribution of the three
isoforms. Rheb is a Ras-like
GTPase that is conserved from yeast to mammals. Rheb is mainly involved in activation of cell growth through stimulation of
mTORC1 activity. In this review, we summarise multidimensional NMR studies on Rheb and Ras carried out to characterise their structure-function relationship and explain how the activity of these
small GTPases can be modulated by low molecular weight compounds. These might help to design
GTPase-selective antagonists for treatment of
cancer and
brain disease.