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Review
. 2025 Sep 1;33(5):758-769.
doi: 10.4062/biomolther.2025.079. Epub 2025 Aug 6.

Arrestins as Possible Drug Targets

Zeynep Nur Cinviz  1 , Elisabetta Moroni  2 , Ozge Sensoy  1   3 , Giulia Morra  2 , Vsevolod V Gurevich  4
Affiliations
Review

Arrestins as Possible Drug Targets

Zeynep Nur Cinviz et al. Biomol Ther (Seoul). .

Abstract

Out of at least 20,000 human proteins fewer than 700 are targeted by drugs. Arrestins regulate G protein-coupled receptors, the largest family of signaling proteins in animals, as well as many receptor-independent signaling pathways. Humans express four arrestin subtypes, two of which are ubiquitous and were already shown to serve as versatile hubs of cellular signaling. So far, arrestin proteins are not directly targeted by any drugs. Here we describe potential targets on arrestins and/or interacting proteins, possible approaches for the development of targeting compounds, expected biological outcomes, and possible research and therapeutic value of targeting the interactions of arrestins with receptors and other signaling and trafficking proteins.

Keywords: Arrestin; Cell signaling; Drug target; GPCR.

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Figures

Fig. 1
Fig. 1
Conformational rearrangements in arrestins upon GPCR binding. The molecule of arrestin-3 (PDB ID: 3P2D (basal arrestin), 6TKO (receptor-bound arrestin) with the conformational rearrangements of particular regions associated with GPCR binding shown in close-ups A through F.
Fig. 2
Fig. 2
AP2 interactions with arrestin and barbadin. The surface of β-appendage of AP2 (PDB ID: 2IV8) is shown in yellow. C-terminus of interacting arrestin-2 is shown in green, the ball-and-stick model of barbadin is colored by elements.
Fig. 3
Fig. 3
Structural basis of arrestin interaction with non-receptor binding partners. (A) The residues of the C-tail that bind clathrin (residue numbering is according to human arrestin-2). (B) The residues that interact with AP2 (residue numbering is according to human arrestin-3). (C) The residues that interact with the N-terminal domain of clathrin (residue numbering is according to human arrestin-2).
Fig. 4
Fig. 4
Known parkin-binding arrestin-3 residues. The structure of arrestin-3 (PDB ID: 3P2D) (Zhan et al., 2011) with residues that interact with parkin shown (Zheng et al., 2025) (residue numbering is according to human arrestin-3). Panels (A), (B), and (C) show enlarged interaction sites on the arrestin-3 surface.
Fig. 5
Fig. 5
Arrestin residues engaged by non-receptor partners. (A) The residues that interact with enolase (residue numbering is according to bovine arrestin-2). (B)The residue that interacts with Raf1 (Arg307) (Coffa et al., 2011b) and MEK1 (Asp26 and Asp29) (Meng et al., 2009) (residue numbering is according to bovine arrestin-2) (Han et al., 2001; Milano et al., 2002). (C) The proline residues that interact with SH3 domains (residue numbering is according to human arrestin-3) (Zhan et al., 2011).
Fig. 6
Fig. 6
Distribution of the pockets that can be targeted by small molecules. (A) Analysis of the crystal structures of basal arrestin-2 and arrestin-3. (B) Analysis of basal arrestin-2 and arrestin-3 molecular dynamics simulations (See Methods). (C) Analysis of the crystal structures of receptor-bound-like arrestin-2 and arrestin-3. The localization of possible pockets is shown on the 3D structure of arrestin-3. (D) Top view. (E) bottom view. The matching colors are used in panels (A-E). (F) The names of the regions shown in panels (A-C).
See this image and copyright information in PMC

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