Structural highlights
FunctionCYH2_HUMAN Acts as a guanine-nucleotide exchange factor (GEF). Promotes guanine-nucleotide exchange on ARF1, ARF3 and ARF6. Promotes the activation of ARF factors through replacement of GDP with GTP. The cell membrane form, in association with ARL4 proteins, recruits ARF6 to the plasma membrane.[1] Publication Abstract from PubMedBy virtual screening using a Fragment-Based Drug Design (FBDD) approach, 33 fragments were selected within small pockets around interaction hot spots on the Sec7 surface of the nucleotide exchange factor Arno, and then their ability to interfere with the Arno-catalyzed nucleotide exchange on the G-protein Arf1 was evaluated. Using SPR, NMR and fluorescence assays, the direct binding of three of the identified fragments to Arno Sec7 domain was demonstrated and the promiscuous aggregate behavior evaluated. Then, the binding mode of one fragment and of a more active analogue was solved by X-ray crystallography. This highlighted the role of stable and transient pockets at the Sec7 domain surface in the discovery and binding of interfering compounds. These results provide structural information on how small organic compounds can interfere with the Arf1-Arno Sec7 domain interaction and may guide the rational drug design of competitive inhibitors of Arno enzymatic activity. Fragment-Based Identification of a Locus in the Sec7 Domain of Arno for the Design of Protein-Protein Interaction Inhibitors.,Jad R, Hoh F, Estaran S, Henriquet C, Boublik Y, Kerkour A, Trouillard R, Martinez J, Pugniere M, Padilla A, Chavanieu A J Med Chem. 2013 Oct 11. PMID:24112024[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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