Epitopes described in "Activation and allosteric modulation of a muscarinic acetylcholine receptor."

Article Authors:Andrew C Kruse; Aaron M Ring; Aashish Manglik; Jianxin Hu; Kelly Hu; Katrin Eitel; Harald Hübner; Els Pardon; Celine Valant; Patrick M Sexton; Arthur Christopoulos; Christian C Felder; Peter Gmeiner; Jan Steyaert; William I Weis; K Christopher Garcia; Jürgen Wess; Brian K Kobilka
Article Title:Activation and allosteric modulation of a muscarinic acetylcholine receptor.
Reference Detail
Reference ID:1027012
Abstract: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 2 adrenergic receptor (2AR) 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 2AR 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.
Affiliations:1] Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, California 94305, USA [2].
Reference Type:Literature
PubMed ID:24256733
Journal Volume:504
Article Pages:101-6
Journal ISSN:1476-4687
Article Chemical List:Isoxazoles;Quaternary Ammonium Compounds;Receptors, Muscarinic;iperoxo
Article MeSH List:Allosteric Regulation; Binding Sites; Cytoplasm(metabolism); Humans; Isoxazoles(chemistry; metabolism); Models, Molecular; Protein Binding; Protein Structure, Tertiary; Quaternary Ammonium Compounds(chemistry; metabolism); Receptors, Muscarinic(chemistry; metabolism)
Curation Last Updated:2015-06-07 20:30:25