Structure and dynamics of the M3 muscarinic acetylcholine receptor

Andrew C. Kruse, Jianxin Hu, Albert C. Pan, Daniel H. Arlow, Daniel M. Rosenbaum, Erica Rosemond, Hillary F. Green, Tong Liu, Pil Seok Chae, Ron O. Dror, David E. Shaw, William I. Weis, Jürgen Wess, Brian K. Kobilka

Research output: Contribution to journalArticle

530 Citations (Scopus)

Abstract

Acetylcholine, the first neurotransmitter to be identified, exerts many of its physiological actions via activation of a family of G-protein-coupled receptors (GPCRs) known as muscarinic acetylcholine receptors (mAChRs). Although the five mAChR subtypes (M1-M5) share a high degree of sequence homology, they show pronounced differences in G-protein coupling preference and the physiological responses they mediate. Unfortunately, despite decades of effort, no therapeutic agents endowed with clear mAChR subtype selectivity have been developed to exploit these differences. We describe here the structure of the G q/11-coupled M3 mAChR ( M3 receptor', from rat) bound to the bronchodilator drug tiotropium and identify the binding mode for this clinically important drug. This structure, together with that of the G i/o-coupled M2 receptor, offers possibilities for the design of mAChR subtype-selective ligands. Importantly, the M3 receptor structure allows a structural comparison between two members of a mammalian GPCR subfamily displaying different G-protein coupling selectivities. Furthermore, molecular dynamics simulations suggest that tiotropium binds transiently to an allosteric site en route to the binding pocket of both receptors. These simulations offer a structural view of an allosteric binding mode for an orthosteric GPCR ligand and provide additional opportunities for the design of ligands with different affinities or binding kinetics for different mAChR subtypes. Our findings not only offer insights into the structure and function of one of the most important GPCR families, but may also facilitate the design of improved therapeutics targeting these critical receptors.

Original languageEnglish (US)
Pages (from-to)552-556
Number of pages5
JournalNature
Volume482
Issue number7386
DOIs
StatePublished - Feb 23 2012

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Muscarinic Receptors
G-Protein-Coupled Receptors
Ligands
GTP-Binding Proteins
Allosteric Site
Bronchodilator Agents
Molecular Dynamics Simulation
Sequence Homology
Pharmaceutical Preparations
Acetylcholine
Neurotransmitter Agents
Therapeutics
Tiotropium Bromide

ASJC Scopus subject areas

  • General

Cite this

Kruse, A. C., Hu, J., Pan, A. C., Arlow, D. H., Rosenbaum, D. M., Rosemond, E., ... Kobilka, B. K. (2012). Structure and dynamics of the M3 muscarinic acetylcholine receptor. Nature, 482(7386), 552-556. https://doi.org/10.1038/nature10867

Structure and dynamics of the M3 muscarinic acetylcholine receptor. / Kruse, Andrew C.; Hu, Jianxin; Pan, Albert C.; Arlow, Daniel H.; Rosenbaum, Daniel M.; Rosemond, Erica; Green, Hillary F.; Liu, Tong; Chae, Pil Seok; Dror, Ron O.; Shaw, David E.; Weis, William I.; Wess, Jürgen; Kobilka, Brian K.

In: Nature, Vol. 482, No. 7386, 23.02.2012, p. 552-556.

Research output: Contribution to journalArticle

Kruse, AC, Hu, J, Pan, AC, Arlow, DH, Rosenbaum, DM, Rosemond, E, Green, HF, Liu, T, Chae, PS, Dror, RO, Shaw, DE, Weis, WI, Wess, J & Kobilka, BK 2012, 'Structure and dynamics of the M3 muscarinic acetylcholine receptor', Nature, vol. 482, no. 7386, pp. 552-556. https://doi.org/10.1038/nature10867
Kruse AC, Hu J, Pan AC, Arlow DH, Rosenbaum DM, Rosemond E et al. Structure and dynamics of the M3 muscarinic acetylcholine receptor. Nature. 2012 Feb 23;482(7386):552-556. https://doi.org/10.1038/nature10867
Kruse, Andrew C. ; Hu, Jianxin ; Pan, Albert C. ; Arlow, Daniel H. ; Rosenbaum, Daniel M. ; Rosemond, Erica ; Green, Hillary F. ; Liu, Tong ; Chae, Pil Seok ; Dror, Ron O. ; Shaw, David E. ; Weis, William I. ; Wess, Jürgen ; Kobilka, Brian K. / Structure and dynamics of the M3 muscarinic acetylcholine receptor. In: Nature. 2012 ; Vol. 482, No. 7386. pp. 552-556.
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