Crystal structure of arrestin-3 reveals the basis of the difference in receptor binding between two non-visual subtypes.

Publication Type:

Journal Article


J Mol Biol, Volume 406, Issue 3, p.467-78 (2011)


Animals, Arrestins, Binding Sites, Cattle, Crystallization, Protein Binding, Protein Conformation, Protein Structure, Tertiary, Receptors, G-Protein-Coupled, Structure-Activity Relationship


<p>Arrestins are multi-functional proteins that regulate signaling and trafficking of the majority of G protein-coupled receptors (GPCRs), as well as sub-cellular localization and activity of many other signaling proteins. We report the first crystal structure of arrestin-3, solved at 3.0 Å resolution. Arrestin-3 is an elongated two-domain molecule with overall fold and key inter-domain interactions that hold the free protein in the basal conformation similar to the other subtypes. Arrestin-3 is the least selective member of the family, binding a wide variety of GPCRs with high affinity and demonstrating lower preference for active phosphorylated forms of the receptors. In contrast to the other three arrestins, part of the receptor-binding surface in the arrestin-3 C-domain does not form a contiguous β-sheet, which is consistent with increased flexibility. By swapping the corresponding elements between arrestin-2 and arrestin-3 we show that the presence of this loose structure is correlated with reduced arrestin selectivity for activated receptors, consistent with a conformational change in this β-sheet upon receptor binding.</p>