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Structure of the M5 muscarinic acetylcholine receptor (M5-T4L) bound to tiotropium
Structural highlights
FunctionD9IEF7_BPT4 ACM5_HUMAN The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the action of G proteins. Primary transducing effect is Pi turnover. Publication Abstract from PubMedThe human M5 muscarinic acetylcholine receptor (mAChR) has recently emerged as an exciting therapeutic target for treating a range of disorders, including drug addiction. However, a lack of structural information for this receptor subtype has limited further drug development and validation. Here we report a high-resolution crystal structure of the human M5 mAChR bound to the clinically used inverse agonist, tiotropium. This structure allowed for a comparison across all 5 mAChR family members that revealed important differences in both orthosteric and allosteric sites that could inform the rational design of selective ligands. These structural studies, together with chimeric swaps between the extracellular regions of the M2 and M5 mAChRs, provided structural insight into kinetic selectivity, where ligands show differential residency times between related family members. Collectively, our study provides important insights into the nature of orthosteric and allosteric ligand interaction across the mAChR family that could be exploited for the design of selective drugs. Crystal structure of the M5 muscarinic acetylcholine receptor.,Vuckovic Z, Gentry PR, Berizzi AE, Hirata K, Varghese S, Thompson G, van der Westhuizen ET, Burger WAC, Rahmani R, Valant C, Langmead CJ, Lindsley CW, Baell JB, Tobin AB, Sexton PM, Christopoulos A, Thal DM Proc Natl Acad Sci U S A. 2019 Nov 26. pii: 1914446116. doi:, 10.1073/pnas.1914446116. PMID:31772027[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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