Activation and allosteric modulation of a muscarinic acetylcholine receptor.

TitleActivation and allosteric modulation of a muscarinic acetylcholine receptor.
Publication TypeJournal Article
Year of Publication2013
AuthorsKruse, A. C., A. M. Ring, A. Manglik, J. Hu, K. Hu, K. Eitel, H. Hübner, E. Pardon, C. Valant, P. M. Sexton, A. Christopoulos, C. C. Felder, P. Gmeiner, J. Steyaert, W. I. Weis, C. K Garcia, J. Wess, and B. K. Kobilka
Date Published2013 Dec 05
KeywordsAllosteric Regulation, Binding Sites, Cytoplasm, Humans, Isoxazoles, Models, Molecular, Protein Binding, Protein Structure, Tertiary, Quaternary Ammonium Compounds, Receptors, Muscarinic

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.

Alternate JournalNature
PubMed ID24256733
PubMed Central IDPMC4020789
Grant ListU19 GM106990 / GM / NIGMS NIH HHS / United States
GM08311806 / GM / NIGMS NIH HHS / United States
T32 GM008294 / GM / NIGMS NIH HHS / United States
/ / Intramural NIH HHS / United States
NS02847123 / NS / NINDS NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
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