A complex structure of arrestin-2 bound to a G protein-coupled receptor

Abstract

Arrestins comprise a family of signal regulators of G-protein-coupled receptors (GPCRs), which include arrestins 1 to 4. While arrestins 1 and 4 are visual arrestins dedicated to rhodopsin, arrestins 2 and 3 (Arr2 and Arr3) are β-arrestins known to regulate many nonvisual GPCRs. The dynamic and promiscuous coupling of Arr2 to nonvisual GPCRs has posed technical challenges to tackle the basis of arrestin binding to GPCRs. Here we report the structure of Arr2 in complex with neurotensin receptor 1 (NTSR1), which reveals an overall assembly that is strikingly different from the visual arrestin-rhodopsin complex by a 90° rotation of Arr2 relative to the receptor. In this new configuration, intracellular loop 3 (ICL3) and transmembrane helix 6 (TM6) of the receptor are oriented toward the N-terminal domain of the arrestin, making it possible for GPCRs that lack the C-terminal tail to couple Arr2 through their ICL3. Molecular dynamics simulation and crosslinking data further support the assembly of the Arr2-NTSR1 complex. Sequence analysis and homology modeling suggest that the Arr2-NTSR1 complex structure may provide an alternative template for modeling arrestin-GPCR interactions.

Distinct phosphorylation sites in a prototypical GPCR differently orchestrate β-arrestin interaction, trafficking, and signaling

“…5A. While Thr 359 is not involved in any interaction with Lys/Arg in arrs, Thr 360 interacts with Arg 25 in  strand II and Lys 294 in the lariat loop ( Fig. 5A).…”

Structure and function of β-arrestins, their emerging role in breast cancer, and potential opportunities for therapeutic manipulation

“…Multiple structures of βarrs are now described in literature including an active conformation of βarr1 in complex with a phosphorylated peptide corresponding to the carboxyl-terminus of the vasopressin V2 receptor (Shukla et al, 2013). In addition, a low-resolution architecture of a chimeric β2 adrenergic receptor with βarr1 (Shukla, Westfield, et al, 2014) and a cryo-EM structure of the neurotensin receptor-βarr1 fusion protein (Yin et al, 2019) have also been described. These studies have started to provide direct structural insights into GPCR-βarr interaction and activation mechanisms although high-resolution structural details on GPCR-βarr complexes are still awaited.…”

Opioid Pharmacology under the Microscope

“…A pioneering example was the determination of a structure of agonist-activated MOP-R in complex with Gi (Koehl et al, 2018). Recently, cryo-electron microscopy was used successfully for structural determination of agonist-activated GPCRs in association with β-arrestin, a physiologically important complex that has eluded conventional xray crystallography (Zhou et al, 2016;Yin et al, 2019;Huang et al, 2020;Staus et al, 2020). It has also enabled structural determination of a GPCR bound to both β-arrestin and G protein simultaneously, a complex which has been proposed to form on the endosome membrane and transduce a sustained form of signaling by certain GPCRs after they undergo ligand-induced internalization (Vilardaga et al, 2012;Nguyen et al, 2019).…”