Structure of the human M2 muscarinic acetylcholine receptor bound to an antagonist View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2012-01-25

AUTHORS

Kazuko Haga, Andrew C. Kruse, Hidetsugu Asada, Takami Yurugi-Kobayashi, Mitsunori Shiroishi, Cheng Zhang, William I. Weis, Tetsuji Okada, Brian K. Kobilka, Tatsuya Haga, Takuya Kobayashi

ABSTRACT

The parasympathetic branch of the autonomic nervous system regulates the activity of multiple organ systems. Muscarinic receptors are G-protein-coupled receptors that mediate the response to acetylcholine released from parasympathetic nerves. Their role in the unconscious regulation of organ and central nervous system function makes them potential therapeutic targets for a broad spectrum of diseases. The M2 muscarinic acetylcholine receptor (M2 receptor) is essential for the physiological control of cardiovascular function through activation of G-protein-coupled inwardly rectifying potassium channels, and is of particular interest because of its extensive pharmacological characterization with both orthosteric and allosteric ligands. Here we report the structure of the antagonist-bound human M2 receptor, the first human acetylcholine receptor to be characterized structurally, to our knowledge. The antagonist 3-quinuclidinyl-benzilate binds in the middle of a long aqueous channel extending approximately two-thirds through the membrane. The orthosteric binding pocket is formed by amino acids that are identical in all five muscarinic receptor subtypes, and shares structural homology with other functionally unrelated acetylcholine binding proteins from different species. A layer of tyrosine residues forms an aromatic cap restricting dissociation of the bound ligand. A binding site for allosteric ligands has been mapped to residues at the entrance to the binding pocket near this aromatic cap. The structure of the M2 receptor provides insights into the challenges of developing subtype-selective ligands for muscarinic receptors and their propensity for allosteric regulation. More... »

PAGES

547-551

Journal

TITLE

Nature

ISSUE

7386

VOLUME

482

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/nature10753

DOI

http://dx.doi.org/10.1038/nature10753

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1031262339

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/22278061


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33 schema:description The parasympathetic branch of the autonomic nervous system regulates the activity of multiple organ systems. Muscarinic receptors are G-protein-coupled receptors that mediate the response to acetylcholine released from parasympathetic nerves. Their role in the unconscious regulation of organ and central nervous system function makes them potential therapeutic targets for a broad spectrum of diseases. The M2 muscarinic acetylcholine receptor (M2 receptor) is essential for the physiological control of cardiovascular function through activation of G-protein-coupled inwardly rectifying potassium channels, and is of particular interest because of its extensive pharmacological characterization with both orthosteric and allosteric ligands. Here we report the structure of the antagonist-bound human M2 receptor, the first human acetylcholine receptor to be characterized structurally, to our knowledge. The antagonist 3-quinuclidinyl-benzilate binds in the middle of a long aqueous channel extending approximately two-thirds through the membrane. The orthosteric binding pocket is formed by amino acids that are identical in all five muscarinic receptor subtypes, and shares structural homology with other functionally unrelated acetylcholine binding proteins from different species. A layer of tyrosine residues forms an aromatic cap restricting dissociation of the bound ligand. A binding site for allosteric ligands has been mapped to residues at the entrance to the binding pocket near this aromatic cap. The structure of the M2 receptor provides insights into the challenges of developing subtype-selective ligands for muscarinic receptors and their propensity for allosteric regulation.
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40 schema:keywords M2 muscarinic acetylcholine receptors
41 M2 receptors
42 acetylcholine
43 acetylcholine receptors
44 acid
45 activation
46 activity
47 allosteric ligands
48 allosteric regulation
49 amino acids
50 antagonist
51 antagonist-bound human M2 receptor
52 aqueous channels
53 aromatic cap
54 autonomic nervous system
55 binds
56 branches
57 broad spectrum
58 cap
59 central nervous system function
60 challenges
61 channels
62 characterization
63 control
64 different species
65 disease
66 dissociation
67 entrance
68 extensive pharmacological characterization
69 first human acetylcholine receptor
70 function
71 homology
72 human M2 muscarinic acetylcholine receptor
73 human M2 receptors
74 human acetylcholine receptor
75 insights
76 interest
77 knowledge
78 layer
79 layer of tyrosine
80 ligands
81 long aqueous channel
82 membrane
83 middle
84 multiple organ systems
85 muscarinic acetylcholine receptors
86 muscarinic receptor subtypes
87 muscarinic receptors
88 nerve
89 nervous system
90 nervous system function
91 organ systems
92 organs
93 parasympathetic branches
94 parasympathetic nerves
95 particular interest
96 pharmacological characterization
97 physiological control
98 pocket
99 potassium channels
100 potential therapeutic target
101 propensity
102 protein
103 protein-coupled receptors
104 receptor subtypes
105 receptors
106 regulation
107 residues
108 response
109 role
110 sites
111 species
112 spectra
113 structural homology
114 structure
115 subtype-selective ligands
116 subtypes
117 system
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121 two-thirds
122 tyrosine
123 unconscious regulation
124 unrelated acetylcholine
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