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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

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Molecular basis of β-arrestin coupling to formoterol-bound β1-adrenoceptor.

Lee Yang Y Warne Tony T Nehmé Rony R Pandey Shubhi S Dwivedi-Agnihotri Hemlata H Chaturvedi Madhu M Edwards Patricia C PC García-Nafría Javier J Leslie Andrew G W AGW Shukla Arun K AK Tate Christopher G CG

Nature 20200617 7818

The β1-adrenoceptor (β1AR) 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 β-arrestin 1 (βarr1, also known as arrestin 2), which displaces Gs and induces signalling through the MAP kinase pathway2. The ability of synthetic agonists to induce signalling p ...[more]

PMID: 32555462

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Project description:Mitochondrial dysfunction is a common mediator of disease and organ injury. Although recent studies show that inducing mitochondrial biogenesis (MB) stimulates cell repair and regeneration, only a limited number of chemicals are known to induce MB. To examine the impact of the β-adrenoceptor (β-AR) signaling pathway on MB, primary renal proximal tubule cells (RPTC) and adult feline cardiomyocytes were exposed for 24 h to multiple β-AR agonists: isoproterenol (nonselective β-AR agonist), (±)-(R*,R*)-[4-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]phenoxy] acetic acid sodium hydrate (BRL 37344) (selective β(3)-AR agonist), and formoterol (selective β(2)-AR agonist). The Seahorse Biosciences (North Billerica, MA) extracellular flux analyzer was used to quantify carbonylcyanide p-trifluoromethoxyphenylhydrazone (FCCP)-uncoupled oxygen consumption rate (OCR), a marker of maximal electron transport chain activity. Isoproterenol and BRL 37244 did not alter mitochondrial respiration at any of the concentrations examined. Formoterol exposure resulted in increases in both FCCP-uncoupled OCR and mitochondrial DNA (mtDNA) copy number. The effect of formoterol on OCR in RPTC was inhibited by the β-AR antagonist propranolol and the β(2)-AR inverse agonist 3-(isopropylamino)-1-[(7-methyl-4-indanyl)oxy]butan-2-ol hydrochloride (ICI-118,551). Mice exposed to formoterol for 24 or 72 h exhibited increases in kidney and heart mtDNA copy number, peroxisome proliferator-activated receptor γ coactivator 1α, and multiple genes involved in the mitochondrial electron transport chain (F0 subunit 6 of transmembrane F-type ATP synthase, NADH dehydrogenase subunit 1, NADH dehydrogenase subunit 6, and NADH dehydrogenase [ubiquinone] 1β subcomplex subunit 8). Cheminformatic modeling, virtual chemical library screening, and experimental validation identified nisoxetine from the Sigma Library of Pharmacologically Active Compounds and two compounds from the ChemBridge DIVERSet that increased mitochondrial respiratory capacity. These data provide compelling evidence for the use and development of β(2)-AR ligands for therapeutic MB.

Dataset Information

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

Publications

Molecular basis of β-arrestin coupling to formoterol-bound β<sub>1</sub>-adrenoceptor.

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