Muscarinic receptors consist of 5 G protein-coupled receptors which along with nicotinic ion channels mediate the effects of acetylcholine. Despite years of research on the role of muscarinic receptors in the brain and periphery the Muscarinic M5 receptor has stood out in contrast to M1 -M4 as one which we know little about. The M5 receptor has a unique and unusual distribution in the brain being enriched in mid brain dopamine neurons and in the cerebellum. A lack of selective chemical tools has hampered our ability to study the function of the receptor. Now Vuckovic et al.  have solved the X-ray crystal structure of the M5 receptor in complex with the non-selective antagonist tiotropium in the presence of a conformational stabilizing mutation. Since tiotropium was also used to solve the structure of several other muscarinic receptors a direct comparison can be made across the subtypes which will enable the design of selective tool compounds. Significant progress has been made in utilizing crystal structures to design selective orthosteric and allosteric ligands at this family of receptors. This final structure completes the set of muscarinic receptor structures solved and hopefully will pave the way to further understanding of the biology of M5 and its role in disorders such as drug addiction and depression.
Comments by Fiona H. Marshall, Discovery Research UK, MSD (@aston_fm)
(1) Vuckovic Z et al. (2019). Crystal Structure of the M5 Muscarinic Acetylcholine Receptor. Proc Natl Acad Sci USA, DOI: 10.1073/pnas.1914446116. [PMID: 31772027]