Structure and Dynamics of the M3 Muscarinic Acetylcholine Receptor

By A. Kruse, Jianxin Hu, Albert C. Pan, Daniel H Arlow, D. Rosenbaum, Erica Rosemond, Hillary F. Green, Tong Liu, P. S. Chae, Ron O. Dror and 4 more. Nature, 2012

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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 Gq/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 Gi/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.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/b7ef6182f90867d0cd1d71eaf9d6c83856c519c4

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Citations in the corpus

Multiple conformational states in retrospective virtual screening – homology models vs. crystal structures: beta-2 adrenergic receptor case study (2015, neutral): “M3R 4DAJ [31] 3.”
Bridging Molecular Docking to Molecular Dynamics in Exploring Ligand-Protein Recognition Process: An Overview (2018, background): “…was observed to recognize the extracellular vestibule of the receptor, as in a previously reported long (16 µ s) classical MD simulation ( Kruse et al., 2012), by accelerating the process of about one order of magnitude (three aMD replicas of 200 ns, 500 ns, and 1 µ s) (Kappel et al.,…”
The Molecular Basis of G Protein–Coupled Receptor Activation (2018, background): “can occlude the orthosteric ligand–binding site from the extracellular milieu and thereby affect the kinetics of ligand binding (20, 21).”
Ligand–receptor interaction platforms and their applications for drug discovery (2012, background): “These include rhodopsin [124], b2-adrenergic receptor [125], b1-adrenergic receptor [126], adenosine A2A receptor [127], CXCR4 chemokine receptor [128], dopamine D3 receptor [129], histamine H1 receptor [130], sphingosine 1-phosphate S1P1 receptor [131], muscarinic M3 acetylcholine receptor [132], m”
5-HT2C Receptor Structures Reveal the Structural Basis of GPCR Polypharmacology (2018, neutral): “, 2011) and muscarinic acetylcholine receptors (Kruse et al., 2012; Thal et al., 2016), respectively.”
Structure-Function of the G-protein-Coupled Receptor Superfamily (2012, background): “48 side chain in most GPCR structures that have been solved, this passage is more open in the muscarinic M2 and M3 receptors (30, 31).”
Assessment and Challenges of Ligand Docking into Comparative Models of G-Protein Coupled Receptors (2013, neutral): “…b 1-adrenergic [15], b 2-adrenergic [16], A2A adenosine [17], CXCR4 chemokine [18], dopamine D3 [19], histamine H1 [20], S1P1 sphingosine 1-phosphate [21], M2 muscarinc acetylcholine [22], M3 muscarinic acetylecholine [23], mu-opioid [24], kappa-opioid [25], N/OFQ opioid [26] and delta-opioid [27].”
Structure-based drug screening for G-protein-coupled receptors. (2012, background): “Since the initial crystal structures of the β2AR[11] and the β1AR[12], the number of published GPCRs which have yielded to crystallography has grown to ten and includes the adenosine A2A receptor[13], the D3 dopamine receptor[14], the CXCR4 receptor [15], the histamine H1 receptor, [16], the sphingo”