Structure-function studies of muscarinic acetylcholine receptors

Katie Leach, John Simms, Patrick M. Sexton, Arthur Christopoulos*

*Corresponding author for this work

Research output: Chapter in Book/Report/Conference proceedingChapter

Abstract

There has been great interest in the structure-function relationships of the muscarinic acetylcholine receptors (mAChRs) because these prototypical Family A/class 1 G protein-coupled receptors (GPCRs) are attractive therapeutic targets for both peripheral and central nervous system disorders. A multitude of drugs that act at the mAChRs have been identified over the years, but many of these show minimal selectivity for any one of the five mAChR subtypes over the others, which has hampered their development into therapeutics due to adverse side effects. The lack of drug specificity is primarily due to high sequence similarity in this family of receptor, especially in the orthosteric binding pocket. Thus, there remains an ongoing need for a molecular understanding of how mAChRs bind their ligands, and how selectivity in binding and activation can be achieved. Unfortunately, there remains a paucity of solved high-resolution structures of GPCRs, including the mAChRs, and thus most of our knowledge of structure-function mechanisms related to this receptor family to date has been obtained indirectly through approaches such as mutagenesis. Nonetheless, such studies have revealed a wealth of information that has led to novel insights and may be used to guide future rational drug design campaigns.

Original languageEnglish
Title of host publicationMuscarinic Receptors
EditorsAllison D. Fryer, Neil M. Nathanson, Arthur Christopoulos
Pages29-48
Number of pages20
DOIs
Publication statusPublished - 10 Feb 2012

Publication series

NameHandbook of Experimental Pharmacology
Volume208
ISSN (Print)0171-2004
ISSN (Electronic)1865-0325

Keywords

  • Allosteric
  • Molecular modeling
  • Muscarinic receptor
  • Mutagenesis
  • Orthosteric
  • Structure-function

Fingerprint Dive into the research topics of 'Structure-function studies of muscarinic acetylcholine receptors'. Together they form a unique fingerprint.

  • Cite this

    Leach, K., Simms, J., Sexton, P. M., & Christopoulos, A. (2012). Structure-function studies of muscarinic acetylcholine receptors. In A. D. Fryer, N. M. Nathanson, & A. Christopoulos (Eds.), Muscarinic Receptors (pp. 29-48). (Handbook of Experimental Pharmacology; Vol. 208). https://doi.org/10.1007/978-3-642-23274-9_2