Molecular basis of ?-arrestin coupling to formoterol-bound ?1-adrenoceptor.

ABSTRACT: The ?1-adrenoceptor (?1AR) is a G-protein-coupled receptor (GPCR) that couples1 to the heterotrimeric G protein Gs. G-protein-mediated signalling is terminated by phosphorylation of the C terminus of the receptor by GPCR kinases (GRKs) and by coupling of ?-arrestin 1 (?arr1, also known as arrestin 2), which displaces Gs and induces signalling through the MAP kinase pathway2. The ability of synthetic agonists to induce signalling preferentially through either G proteins or arrestins-known as biased agonism3-is important in drug development, because the therapeutic effect may arise from only one signalling cascade, whereas the other pathway may mediate undesirable side effects4. To understand the molecular basis for arrestin coupling, here we determined the cryo-electron microscopy structure of the ?1AR-?arr1 complex in lipid nanodiscs bound to the biased agonist formoterol5, and the crystal structure of formoterol-bound ?1AR coupled to the G-protein-mimetic nanobody6 Nb80. ?arr1 couples to ?1AR in a manner distinct to that7 of Gs coupling to ?2AR-the finger loop of ?arr1 occupies a narrower cleft on the intracellular surface, and is closer to transmembrane helix H7 of the receptor when compared with the C-terminal ?5 helix of Gs. The conformation of the finger loop in ?arr1 is different from that adopted by the finger loop of visual arrestin when it couples to rhodopsin8. ?1AR coupled to ?arr1 shows considerable differences in structure compared with ?1AR coupled to Nb80, including an inward movement of extracellular loop 3 and the cytoplasmic ends of H5 and H6. We observe weakened interactions between formoterol and two serine residues in H5 at the orthosteric binding site of ?1AR, and find that formoterol has a lower affinity for the ?1AR-?arr1 complex than for the ?1AR-Gs complex. The structural differences between these complexes of ?1AR provide a foundation for the design of small molecules that could bias signalling in the ?-adrenoceptors.

SUBMITTER: Lee Y 

PROVIDER: S-EPMC7115876 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature