Structure-function studies of muscarinic acetylcholine receptors

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

Research output: Chapter in Book/Report/Conference proceedingChapter

13 Citations (Scopus)

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
PublisherSpringer Verlag
Pages29-48
Number of pages20
ISBN (Electronic)9783642232749
ISBN (Print)9783642237232
DOIs
Publication statusPublished - 2012

Publication series

NameHandbook of Experimental Pharmacoloy
PublisherSpringer
Volume208

Fingerprint

Muscarinic Receptors
G-Protein-Coupled Receptors
Drug Design
Central Nervous System Diseases
Peripheral Nervous System Diseases
Mutagenesis
Pharmaceutical Preparations
Ligands
Therapeutics

Keywords

  • Acetylcholine
  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Humans
  • Ligands
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation
  • Protein Conformation
  • Receptors, Muscarinic
  • Signal Transduction
  • Structure-Activity Relationship
  • Journal Article
  • Research Support, Non-U.S. Gov't
  • Review

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 Pharmacoloy; Vol. 208). Springer Verlag. https://doi.org/10.1007/978-3-642-23274-9_2

Structure-function studies of muscarinic acetylcholine receptors. / Leach, Katie; Simms, John; Sexton, Patrick M; Christopoulos, Arthur.

Muscarinic Receptors. ed. / Allison D. Fryer; Neil M. Nathanson; Arthur Christopoulos. Springer Verlag, 2012. p. 29-48 (Handbook of Experimental Pharmacoloy; Vol. 208).

Research output: Chapter in Book/Report/Conference proceedingChapter

Leach, K, Simms, J, Sexton, PM & Christopoulos, A 2012, Structure-function studies of muscarinic acetylcholine receptors. in AD Fryer, NM Nathanson & A Christopoulos (eds), Muscarinic Receptors. Handbook of Experimental Pharmacoloy, vol. 208, Springer Verlag, pp. 29-48. https://doi.org/10.1007/978-3-642-23274-9_2
Leach K, Simms J, Sexton PM, Christopoulos A. Structure-function studies of muscarinic acetylcholine receptors. In Fryer AD, Nathanson NM, Christopoulos A, editors, Muscarinic Receptors. Springer Verlag. 2012. p. 29-48. (Handbook of Experimental Pharmacoloy). https://doi.org/10.1007/978-3-642-23274-9_2
Leach, Katie ; Simms, John ; Sexton, Patrick M ; Christopoulos, Arthur. / Structure-function studies of muscarinic acetylcholine receptors. Muscarinic Receptors. editor / Allison D. Fryer ; Neil M. Nathanson ; Arthur Christopoulos. Springer Verlag, 2012. pp. 29-48 (Handbook of Experimental Pharmacoloy).
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AB - 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.

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