Activation and allosteric modulation of a muscarinic acetylcholine receptor

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 and Brian K. Kobilka ()
Additional contact information
Andrew C. Kruse: Stanford University School of Medicine, 279 Campus Drive
Aaron M. Ring: Stanford University School of Medicine, 279 Campus Drive
Aashish Manglik: Stanford University School of Medicine, 279 Campus Drive
Jianxin Hu: Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases
Kelly Hu: Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases
Katrin Eitel: Friedrich Alexander University, Schuhstrasse 19, 91052 Erlangen, Germany
Harald Hübner: Friedrich Alexander University, Schuhstrasse 19, 91052 Erlangen, Germany
Els Pardon: Structural Biology Brussels, Vrije Universiteit Brussel, Pleinlaan 2, B-1050 Brussels, Belgium
Celine Valant: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University
Patrick M. Sexton: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University
Arthur Christopoulos: Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University
Christian C. Felder: Neuroscience, Eli Lilly & Co.
Peter Gmeiner: Friedrich Alexander University, Schuhstrasse 19, 91052 Erlangen, Germany
Jan Steyaert: Structural Biology Brussels, Vrije Universiteit Brussel, Pleinlaan 2, B-1050 Brussels, Belgium
William I. Weis: Stanford University School of Medicine, 279 Campus Drive
K. Christopher Garcia: Stanford University School of Medicine, 279 Campus Drive
Jürgen Wess: Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases
Brian K. Kobilka: Stanford University School of Medicine, 279 Campus Drive

Nature, 2013, vol. 504, issue 7478, 101-106

Abstract: 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 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.

Date: 2013
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DOI: 10.1038/nature12735

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