Allosteric site on muscarinic acetylcholine receptors: identification of two amino acids in the muscarinic M2 receptor that account entirely for the M2/M5 subtype selectivities of some structurally diverse allosteric ligands in N-methylscopolamine-occupied receptors.

@article{Voigtlnder2003AllostericSO,
  title={Allosteric site on muscarinic acetylcholine receptors: identification of two amino acids in the muscarinic M2 receptor that account entirely for the M2/M5 subtype selectivities of some structurally diverse allosteric ligands in N-methylscopolamine-occupied receptors.},
  author={U. Voigtl{\"a}nder and Kirstin J{\"o}hren and M. Mohr and Alexandra Raasch and C. Tr{\"a}nkle and S. Buller and J. Ellis and H. H{\"o}ltje and K. Mohr},
  journal={Molecular pharmacology},
  year={2003},
  volume={64 1},
  pages={
          21-31
        }
}
Two epitopes have been identified recently to be responsible for the high-affinity binding of alkane-bisammonium and caracurine V type allosteric ligands to N-methylscopolamine (NMS)-occupied M2 muscarinic acetylcholine receptors, relative to M5 receptors: the amino acid M2-Thr423 at the top of transmembrane region (TM) 7 and an epitope comprising the second extracellular loop (o2) of the M2 receptor including the flanking regions of TM4 and TM5. We aimed to find out whether a single amino acid… Expand
Allosteric Interactions with Muscarinic Acetylcholine Receptors: Complex Role of the Conserved Tryptophan M2422Trp in a Critical Cluster of Amino Acids for Baseline Affinity, Subtype Selectivity, and Cooperativity
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Allosteric Binding Sites on Muscarinic Acetylcholine Receptors
  • J. Wess
  • Chemistry, Medicine
  • Molecular Pharmacology
  • 2005
TLDR
Evidence is provided suggesting that two allosteric agents and one orthosteric ligand may be able to bind to the M2 mAChR simultaneously, and molecular modeling and ligand docking studies suggested that the additional allosterics site probably represents a subdomain of the receptor'sAllosteric binding cleft. Expand
Critical Amino Acid Residues of the Common Allosteric Site on the M2 Muscarinic Acetylcholine Receptor: More Similarities than Differences between the Structurally Divergent Agents Gallamine and Bis(ammonio)alkane-Type Hexamethylene-bis-[dimethyl-(3-phthalimidopropyl)ammonium]dibromide
TLDR
Gallamine and W84 derive high potency from the same receptor domains (epitopes in o2 and near the junction between o3 and TM7), even though these allosteric agents have quite different structures. Expand
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A differential role of criticalAllosteric site residues on the binding and function of allosteric agonists versus allosterics modulators of M2 mAChRs is revealed. Expand
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This study investigated the pharmacological profile of ASP8302, a novel PAM of M3 receptors, and explored the principal site of amino acid sequences in the human M3 receptor required for the potentiation of receptor activation, and identified threonine 230 as the amino acid essential for the PAM effect. Expand
Structure-function studies of M4 muscarinic acetylcholine receptor allosteric modulation
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These studies demonstrate that a stereochemical difference can be sufficient to translate into divergent epitope sensitivities and are the first time that the subtype selectivity of muscarinic allosteric agents has been completely accounted for by distinct receptor epitopes. Expand
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Site-directed mutagenesis reveals two epitopes involved in the subtype selectivity of the allosteric interactions of gallamine at muscarinic acetylcholine receptors.
TLDR
Analysis of numerous point mutations in this region of the M(5) receptor found that a mutation of V --> N resulted in an increased affinity toward gallamine, suggesting that the asparagine residue at M(2)(419) is responsible for gallamine's M( 2)/M(5] selectivity. Expand
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