Activation and allosteric modulation of a muscarinic acetylcholine receptor

Journal article
(Original article)


Publication Details

Author(s): Kruse AC, Ring AM, Manglik A, Hu J, Hu K, Eitel K, Hübner H, Pardon E, Valant C, Sexton PM, Christopoulos A, Felder CC, Gmeiner P, Steyaert J, Weis WI, Garcia KC, Wess J, Kobilka BK
Journal: Nature
Publisher: Nature Publishing Group
Publication year: 2013
Volume: 504
Pages range: 101-106
ISSN: 0028-0836
Language: English


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 β 2 adrenergic receptor (β 2 AR) 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 β 2 AR 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. © 2013 Macmillan Publishers Limited. All rights reserved.



FAU Authors / FAU Editors

Eitel, Katrin
Lehrstuhl für Pharmazeutische Chemie
Gmeiner, Peter Prof. Dr.
Lehrstuhl für Pharmazeutische Chemie
Hübner, Harald Dr.
Lehrstuhl für Pharmazeutische Chemie


Additional Organisation
Emil-Fischer-Zentrum (Emil Fischer Center)


External institutions with authors

Lilly
Monash University
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Stanford University
Vrije Universiteit Brussel


How to cite

APA:
Kruse, A.C., Ring, A.M., Manglik, A., Hu, J., Hu, K., Eitel, K.,... Kobilka, B.K. (2013). Activation and allosteric modulation of a muscarinic acetylcholine receptor. Nature, 504, 101-106. https://dx.doi.org/10.1038/nature12735

MLA:
Kruse, Andrew C., et al. "Activation and allosteric modulation of a muscarinic acetylcholine receptor." Nature 504 (2013): 101-106.

BibTeX: 

Last updated on 2018-10-08 at 22:57