Structural highlights
Function
ARF1_HUMAN GTP-binding protein that functions as an allosteric activator of the cholera toxin catalytic subunit, an ADP-ribosyltransferase. Involved in protein trafficking among different compartments. Modulates vesicle budding and uncoating within the Golgi complex. Deactivation induces the redistribution of the entire Golgi complex to the endoplasmic reticulum, suggesting a crucial role in protein trafficking. In its GTP-bound form, its triggers the association with coat proteins with the Golgi membrane. The hydrolysis of ARF1-bound GTP, which is mediated by ARFGAPs proteins, is required for dissociation of coat proteins from Golgi membranes and vesicles.
Publication Abstract from PubMed
The Ras superfamily of small GTPases are guanine nucleotide dependent switches essential for numerous cellular processes. Mutations or dysregulation of these proteins are associated with many diseases, but unsuccessful attempts to target the small GTPases directly have resulted in them being classed as 'undruggable'. The GTP dependent signaling of these proteins is controlled by their regulators; guanine nucleotide exchange factors (GEFs), GTPase activating proteins (GAPs), and in the Rho and Rab subfamilies, guanine nucleotide dissociation inhibitors (GDIs). This review covers the recent small molecule and biologics strategies to target the small GTPases through their regulators. It seeks to critically re-evaluate recent chemical biology practice, such as the presence of PAINs motifs and the cell-based readout using compounds that are weakly potent or of unknown specificity. It highlights the vast scope of potential approaches for targeting the small GTPases in the future through their regulatory proteins.
Targeting the Small GTPase Superfamily through their Regulatory Proteins.,Gray JL, von Delft F, Brennan P Angew Chem Int Ed Engl. 2019 Mar 14. doi: 10.1002/anie.201900585. PMID:30869179[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Gray JL, von Delft F, Brennan P. Targeting the Small GTPase Superfamily through their Regulatory Proteins. Angew Chem Int Ed Engl. 2019 Mar 14. doi: 10.1002/anie.201900585. PMID:30869179 doi:http://dx.doi.org/10.1002/anie.201900585
