Small monomeric GTPase (Small GTPase)

Small GTPases are a large superfamily of monomeric hydrolase enzymes, typically 20-30 kDa in size, that function as molecular switches to regulate diverse cellular processes (Wennerberg et al., 2005, J Cell Sci). They cycle between an active GTP-bound state and an inactive GDP-bound state, a process tightly controlled by Guanine Nucleotide Exchange Factors (GEFs) and GTPase-Activating Proteins (GAPs) (Cherfils & Zeghouf, 2013, Physiol Rev). The superfamily is divided into five major branches—Ras, Rho, Rab, Arf, and Ran—each governing specific functions such as gene expression, actin remodeling, and vesicle transport (Colicelli, 2004, Sci STKE). Mutations in these proteins, particularly the Ras family, are among the most common drivers of human oncogenesis, leading to constitutive signaling and uncontrolled cell growth (Prior et al., 2020, Cancer Res). Historically labeled as undruggable due to their picomolar affinity for GTP and lack of traditional small-molecule binding pockets, recent therapeutic advances have successfully targeted specific mutants like KRAS G12C using covalent inhibitors (Canon et al., 2019, Nature). Beyond oncology, small GTPases are implicated in neurodegenerative and cardiovascular diseases, making them critical focal points for drug development (Wang et al., 2020, Signal Transduct Target Ther).

Other names

Ras superfamilyMonomeric GTP-binding proteinSmall G-proteinMonomeric GTPase

Covalent inhibition of specific mutant alleles (e.g., KRAS G12C), inhibition of farnesyltransferase to prevent membrane localization, and interference with guanine nucleotide exchange factors (GEFs) or effector interactions (Canon et al., 2019, Nature; Wang et al., 2020, Signal Transduct Target Ther).