Nov 18, 2014

Molecular determinants of β-arrestin coupling to formoterol-bound β1-adrenoceptor

BioRxiv : the Preprint Server for Biology
Dan M BolserChristopher G Tate

Abstract

The β1-adrenoceptor (β1AR) is a G protein-coupled receptor (GPCR) activated by the hormone noradrenaline, resulting in the coupling of the heterotrimeric G protein Gs1. G protein-mediated signalling is terminated by phosphorylation of the receptor C-terminus and 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 preferentially through either G proteins or arrestins (biased agonism)3 is important in drug development, as the therapeutic effect may arise from only one signalling cascade, whilst the other pathway may mediate undesirable side effects4. To understand the molecular basis for arrestin coupling, we determined the electron cryo-microscopy (cryo-EM) structure of the β1AR-βarr1 complex in lipid nanodiscs bound to the biased agonist formoterol5, and the crystal structure of formoterol-bound β1AR coupled to the G protein mimetic nanobody Nb806. βarr1 couples to β1AR in a distinct manner to how Gs couples to β2AR7, with the finger loop of βarr1 occupying a narrower cleft on the intracellular surface closer to transmembrane helix H7 than the C-terminal α5 helix of Gs. The conformation of th...Continue Reading

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