Activation and allosteric modulation of a muscarinic acetylcholine receptor

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 (2013)

Publication Language: English

Publication Type: Journal article, Original article

Publication year: 2013

Journal

Nature Nature Publishing Group

Original Authors: Kruse A.C., Ring A.M., Manglik A., Hu J., Hu K., Eitel K., Hubner H., Pardon E., Valant C., Sexton P.M., Christopoulos A., Felder C.C., Gmeiner P., Steyaert J., Weis W.I., Garcia K.C., Wess J., Kobilka B.K.

Publisher: Nature Publishing Group

Book Volume: 504

Pages Range: 101-106

DOI: 10.1038/nature12735

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.

Authors with CRIS profile

Katrin Eitel Lehrstuhl für Pharmazeutische Chemie Harald Hübner Lehrstuhl für Pharmazeutische Chemie Peter Gmeiner Lehrstuhl für Pharmazeutische Chemie

Additional Organisation(s)

Emil-Fischer-Zentrum (Emil Fischer Center)

Involved external institutions

Vrije Universiteit Brussel (VUB) BE Belgium (BE) National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK / NIDDKD) US United States (USA) (US) Monash University AU Australia (AU) Lilly US United States (USA) (US) Stanford University US United States (USA) (US)

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://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.

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