2012
DOI: 10.1038/nature10867
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Structure and dynamics of the M3 muscarinic acetylcholine receptor

Abstract: Acetylcholine (ACh), the first neurotransmitter to be identified1, exerts many of its physiological actions via activation of a family of G protein-coupled receptors (GPCRs) known as muscarinic ACh receptors (mAChRs). Although the five mAChR subtypes (M1-M5) share a high degree of sequence homology, they show pronounced differences in G protein coupling preference and the physiological responses they mediate.2–4 Unfortunately, despite decades of effort, no therapeutic agents endowed with clear mAChR subtype se… Show more

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Cited by 734 publications
(805 citation statements)
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“…In the GPCRs analyzed, the authors found a correlation between the selectivity of G-protein coupling and the distance between the intracellular termini of TM5 and TM6. This finding is consistent with the idea that the selectivity of GPCR/G protein recognition is determined by both specific interresidue interactions and features related to the overall three-dimensional conformation of the ICD (20). It appears, therefore, that to elucidate the fundamentals of the selectivity of GPCR/G protein recognition, a comprehensive analysis of the structure-activity relationships of multiple GPCR complexes with different G protein isoforms is required.…”
Section: Introductionsupporting
confidence: 86%
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“…In the GPCRs analyzed, the authors found a correlation between the selectivity of G-protein coupling and the distance between the intracellular termini of TM5 and TM6. This finding is consistent with the idea that the selectivity of GPCR/G protein recognition is determined by both specific interresidue interactions and features related to the overall three-dimensional conformation of the ICD (20). It appears, therefore, that to elucidate the fundamentals of the selectivity of GPCR/G protein recognition, a comprehensive analysis of the structure-activity relationships of multiple GPCR complexes with different G protein isoforms is required.…”
Section: Introductionsupporting
confidence: 86%
“…However, when removed from their structural context, isolated peptides may not accurately convey the whole scope of functionalities attributed to the GPCR ICDs. The structural determinants of G protein-coupling specificity may include subtle features of the secondary and tertiary structures (19), which are components of a composite functional epitope comprising sequences distant from each other in the receptor's primary structure (20). It is also possible for some elements of the interaction interface to play a permissive role in recognition (positive specificity) while others exert a prohibitive effect (negative specificity).…”
Section: Discussion Gpcr Mimeticsmentioning
confidence: 99%
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“…62 However, recent publication of the inactive human M 2 and the rat M 3 mAChR crystal structures 63,64 will undoubtedly provide unparalleled insight into the structures of the other muscarinic receptor subtypes going forward.…”
Section: ■ Structural Studies Of M 1 Machr Orthosteric and Allostericmentioning
confidence: 99%