Activation and allosteric modulation of a muscarinic acetylcholine receptor
| Autor: | Patrick M. Sexton, Aaron M. Ring, William I. Weis, Brian K. Kobilka, Els Pardon, Jan Steyaert, Harald Hübner, Jianxin Hu, Christian C. Felder, Kelly Hu, Aashish Manglik, K. Christopher Garcia, Andrew C. Kruse, Peter Gmeiner, Jürgen Wess, Arthur Christopoulos, Celine Valant, Katrin Eitel |
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| Přispěvatelé: | Department of Bio-engineering Sciences, Structural Biology Brussels |
| Rok vydání: | 2013 |
| Předmět: |
Models
Molecular Protein Structure Cytoplasm Allosteric modulator General Science & Technology Allosteric regulation Article 03 medical and health sciences GPCR 0302 clinical medicine Allosteric Regulation Models Receptors Muscarinic Muscarinic acetylcholine receptor M5 Muscarinic acetylcholine receptor Humans 030304 developmental biology G protein-coupled receptor M2R 0303 health sciences Binding Sites Multidisciplinary biology Chemistry Molecular Muscarinic acetylcholine receptor M2 Isoxazoles Receptors Muscarinic Protein Structure Tertiary Quaternary Ammonium Compounds Allosteric enzyme Biochemistry Rhodopsin biology.protein Biophysics Tertiary 030217 neurology & neurosurgery Protein Binding |
| Zdroj: | Nature Nature, vol 504, iss 7478 |
| ISSN: | 1476-4687 0028-0836 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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