Guanosine triphosphatase superfamily (GTPase)

The Guanosine triphosphatase (GTPase) superfamily consists of enzymes that act as molecular switches, cycling between active GTP-bound and inactive GDP-bound states to control cellular signaling (Source: UniProt, 2024). These proteins are essential for diverse biological processes, including signal transduction, protein synthesis, vesicular transport, and cytoskeletal organization (Source: Wikipedia, 2024). The superfamily is divided into several major groups, including the Ras-like small GTPases and the heterotrimeric G proteins associated with cell surface receptors (Source: StatPearls, 2023). Mutations or dysregulation within this superfamily are frequently linked to human diseases, particularly cancer, where Ras mutations are among the most common oncogenic drivers (Source: PubMed, PMID: 31666701). Historically, GTPases were viewed as undruggable because of their extremely high affinity for GTP/GDP and the lack of deep hydrophobic pockets for small-molecule binding (Source: Nature Reviews Drug Discovery, 2014). However, the recent development of covalent inhibitors like sotorasib and adagrasib has revolutionized the field by successfully targeting the KRAS G12C mutation (Source: FDA, 2021). Beyond oncology, GTPases are being explored as targets for cardiovascular and neurodegenerative conditions due to their roles in Rho-kinase signaling and Rab-mediated trafficking (Source: Journal of Biological Chemistry, 2022). Therapeutic strategies now include direct inhibition, targeting regulatory GEFs/GAPs, and interfering with post-translational modifications like prenylation (Source: PubChem, 2024).

Other names

G proteinsGuanosine nucleotide-binding proteinsP-loop NTPasesSmall GTPasesHeterotrimeric G proteins

Covalent inhibition of specific mutant residues (e.g., Cys12 in KRAS), inhibition of farnesyltransferase to prevent membrane localization, and allosteric modulation of regulatory protein interactions (Source: Nature, 2019; PubMed, PMID: 34161023).