Activation and allosteric modulation of a muscarinic acetylcholine receptor

By A. Kruse, A. Ring, A. Manglik, Jianxin Hu, Kelly Hu, K. Eitel, H. Hübner, E. Pardon, C. Valant, P. Sexton and 8 more. Nature, 2013

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Despite recent advances in crystallography and the availability of G-protein-coupled receptor (GPCR) structures, little is known about the mechanism of their activation process, as only the β2 adrenergic receptor (β2AR) and rhodopsin have been crystallized in fully active conformations. Here we report the structure of an agonist-bound, active state of the human M2 muscarinic acetylcholine receptor stabilized by a G-protein mimetic camelid antibody fragment isolated by conformational selection using yeast surface display. In addition to the expected changes in the intracellular surface, the structure reveals larger conformational changes in the extracellular region and orthosteric binding site than observed in the active states of the β2AR and rhodopsin. We also report the structure of the M2 receptor simultaneously bound to the orthosteric agonist iperoxo and the positive allosteric modulator LY2119620. This structure reveals that LY2119620 recognizes a largely pre-formed binding site in the extracellular vestibule of the iperoxo-bound receptor, inducing a slight contraction of this outer binding pocket. These structures offer important insights into the activation mechanism and allosteric modulation of muscarinic receptors.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/64518d2b362afa207ad69dcddacede1e8f8260ce

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Citations in the corpus

Integrating structural and mutagenesis data to elucidate GPCR ligand binding (2016, background): “This vestibule was later found to constitute an allosteric site for the muscarinic M2 receptor positive allosteric modulator (PAM) LY2119620 [19].”
DREADDs for Neuroscientists (2016, background): “Currently there are many high-resolution structures of GPCRs including a 1.8 Å structure of the human δ-opioid receptor (Katritch et al., 2014), two serotonin receptors in partially active states (Wang et al., 2013), active and coupled states of the μ-opioid (Huang et al., 2015a), M1-muscarinic (Kru”
The Molecular Basis of G Protein–Coupled Receptor Activation (2018, methodology): “49 with ICL2 as well as the end of TM2 is seen in several other active structures (32, 34).”
GPCRdb: an information system for G protein-coupled receptors (2015, background): “These have revealed mechanisms of orthosteric and allosteric (9) ligand binding, conformational changes upon receptor activation (10–12), and the modes of binding of G protein (13,14) and -arrestin (15) signal mediators.”
A genetically-encoded fluorescent sensor enables rapid and specific detection of dopamine in flies, fish, and mice (2018, background): “…of the G protein-coupled receptor (GPCR) links transmembrane V and VI that are thought to undergo large conformational changes upon ligand binding (Kruse et al., 2013), a cpEGFP was first inserted into the ICL3 of all five subtypes of human dopamine receptors (DRs); we subsequently focused on the…”