Structure of the human M2 muscarinic acetylcholine receptor bound to an antagonist.

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 0410462 Publication Model: Electronic Cited Medium: Internet ISSN: 1476-4687 (Electronic) Linking ISSN: 00280836 NLM ISO Abbreviation: Nature Subsets: MEDLINE

Publication: Basingstoke : Nature Publishing Group
Original Publication: London, Macmillan Journals ltd.

Cholinergic Antagonists/*chemistry ; Cholinergic Antagonists/*pharmacology ; Quinuclidinyl Benzilate/*analogs & derivatives ; Quinuclidinyl Benzilate/*chemistry ; Quinuclidinyl Benzilate/*pharmacology ; Receptor, Muscarinic M2/*antagonists & inhibitors ; Receptor, Muscarinic M2/*chemistry; Acetylcholine/analogs & derivatives ; Acetylcholine/chemistry ; Acetylcholine/metabolism ; Acetylcholinesterase/chemistry ; Acetylcholinesterase/metabolism ; Allosteric Regulation ; Binding Sites ; Carrier Proteins/chemistry ; Carrier Proteins/metabolism ; Cholinergic Antagonists/metabolism ; Crystallography, X-Ray ; Evolution, Molecular ; Humans ; Ligands ; Models, Molecular ; Protein Conformation ; Quinuclidinyl Benzilate/metabolism ; Receptor, Muscarinic M2/genetics ; Receptor, Muscarinic M2/metabolism ; Tyrosine/chemistry ; Tyrosine/metabolism

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.

Comment in: Nature. 2012 Feb 22;482(7386):480-1. doi: 10.1038/482480a. (PMID: 22358836)

Mol Pharmacol. 2007 Dec;72(6):1484-96. (PMID: 17848601)
Nature. 2011 Jun 22;475(7354):65-70. (PMID: 21697825)
Curr Neuropharmacol. 2007 Sep;5(3):157-67. (PMID: 19305798)
Recept Channels. 2003;9(4):215-28. (PMID: 12893535)
J Biol Chem. 1985 Jul 5;260(13):7927-35. (PMID: 4008482)
Life Sci. 1993;53(19):1447-63. (PMID: 8412508)
Nat Protoc. 2009;4(5):706-31. (PMID: 19390528)
Acta Crystallogr D Biol Crystallogr. 2005 Jul;61(Pt 7):850-5. (PMID: 15983406)
Science. 2008 Nov 21;322(5905):1211-7. (PMID: 18832607)
Microb Cell Fact. 2011 Apr 22;10:24. (PMID: 21513509)
Annu Rev Pharmacol Toxicol. 1990;30:633-73. (PMID: 2188581)
J Biol Chem. 2011 Feb 11;286(6):4420-8. (PMID: 21115477)
Trends Pharmacol Sci. 2002 Jun;23(6):281-7. (PMID: 12084634)
FEBS Lett. 1982 Nov 8;148(2):179-91. (PMID: 6759163)
FEBS Lett. 2006 Jan 9;580(1):23-6. (PMID: 16364317)
J Appl Crystallogr. 2007 Aug 1;40(Pt 4):658-674. (PMID: 19461840)
Mol Pharmacol. 2002 Oct;62(4):778-87. (PMID: 12237324)
Eur J Biochem. 1994 Dec 1;226(2):267-76. (PMID: 8001544)
Science. 2010 Nov 19;330(6007):1066-71. (PMID: 20929726)
Methods Enzymol. 1997;276:307-26. (PMID: 27754618)
Cytotechnology. 2002 Jan;38(1-3):77-85. (PMID: 19003089)
Mol Pharmacol. 1999 Nov;56(5):1031-41. (PMID: 10531410)
Science. 2000 Aug 4;289(5480):739-45. (PMID: 10926528)
J Biol Chem. 2008 Nov 21;283(47):32848-59. (PMID: 18779321)
Science. 2010 Nov 19;330(6007):1091-5. (PMID: 21097933)
Nature. 1985 Aug 22-28;316(6030):731-3. (PMID: 3929139)
Nature. 2011 Jan 13;469(7329):175-80. (PMID: 21228869)
Science. 2007 Nov 23;318(5854):1266-73. (PMID: 17962519)
Nature. 1986 May 1-7;321(6065):75-9. (PMID: 3010132)
J Biol Chem. 1983 Nov 25;258(22):13575-9. (PMID: 6643441)
J Biol Chem. 1994 Jul 22;269(29):18870-6. (PMID: 8034642)
Acta Crystallogr D Biol Crystallogr. 2007 Jan;63(Pt 1):32-41. (PMID: 17164524)
Nat Rev Drug Discov. 2007 Sep;6(9):721-33. (PMID: 17762886)
Eur J Pharmacol. 1999 Sep 10;380(2-3):183-95. (PMID: 10513578)
Nature. 2008 Jul 24;454(7203):486-91. (PMID: 18594507)
EMBO J. 2006 Jun 21;25(12):2746-56. (PMID: 16763558)
Nature. 1986 Oct 2-8;323(6087):411-6. (PMID: 3762692)

GM083118 United States GM NIGMS NIH HHS; R37 NS028471-21 United States NS NINDS NIH HHS; R01 GM083118 United States GM NIGMS NIH HHS; R01 NS028471 United States NS NINDS NIH HHS; R37 NS028471 United States NS NINDS NIH HHS; NS028471 United States NS NINDS NIH HHS

PDB 3UON

0 (AChBP protein, Lymnaea)
0 (Carrier Proteins)
0 (Cholinergic Antagonists)
0 (Ligands)
0 (Receptor, Muscarinic M2)
42HK56048U (Tyrosine)
6581-06-2 (Quinuclidinyl Benzilate)
EC 3.1.1.7 (Acetylcholinesterase)
N9YNS0M02X (Acetylcholine)

Date Created: 20120127 Date Completed: 20120329 Latest Revision: 20211021

20250114

PMC3345277

10.1038/nature10753

22278061