The acetylcholine receptor molecule: allosteric sites and the ion channel

1987 ◽  
Vol 10 (6) ◽  
pp. 245-250 ◽  
Author(s):  
Jean-Pierre Changeux ◽  
Frédéric Revah
Keyword(s):  
Ion Channel ◽  
Acetylcholine Receptor ◽  
Receptor Molecule ◽  
Allosteric Sites

scholarly journals Crystal structure of the M5muscarinic acetylcholine receptor

2019 ◽  
Vol 116 (51) ◽  
pp. 26001-26007 ◽  
Author(s):  
Ziva Vuckovic ◽  
Patrick R. Gentry ◽  
Alice E. Berizzi ◽  
Kunio Hirata ◽  
Swapna Varghese ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Acetylcholine Receptor ◽  
Rational Design ◽  
Structural Information ◽  
Family Members ◽  
Muscarinic Acetylcholine Receptor ◽  
Receptor Subtype ◽  
Ligand Interaction ◽  
Related Family ◽  
Allosteric Sites

The human M5muscarinic 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 M5mAChR 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 M2and M5mAChRs, 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.

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