Binding of N-methylscopolamine to the extracellular domain of muscarinic acetylcholine receptors

@article{Jakubk2017BindingON,
  title={Binding of N-methylscopolamine to the extracellular domain of muscarinic acetylcholine receptors},
  author={J. Jakub{\'i}k and A. Rand{\'a}kov{\'a} and P. Zim{\vc}{\'i}k and E. El-Fakahany and V. Dole{\vz}al},
  journal={Scientific Reports},
  year={2017},
  volume={7}
}
Interaction of orthosteric ligands with extracellular domain was described at several aminergic G protein-coupled receptors, including muscarinic acetylcholine receptors. The orthosteric antagonists quinuclidinyl benzilate (QNB) and N-methylscopolamine (NMS) bind to the binding pocket of the muscarinic acetylcholine receptor formed by transmembrane α-helices. We show that high concentrations of either QNB or NMS slow down dissociation of their radiolabeled species from all five subtypes of… Expand
Allostery of atypical modulators at oligomeric G protein-coupled receptors
TLDR
The results illustrate that oligomerization of the M2 receptor has functional consequences, and indicates that its atypical effects are a property of the receptor in its oligomeric state. Expand
Current Advances in Allosteric Modulation of Muscarinic Receptors
TLDR
Progress made during the last decade in understanding of the mechanisms of binding, allosteric modulation, and in vivo actions of muscarinic receptors is reviewed in order to understand the translational impact of studying this important class of pharmacological agents. Expand
Acetylcholine Neurotransmitter Receptor Densities in the Striatum of Hemiparkinsonian Rats Following Botulinum Neurotoxin-A Injection
TLDR
Novel insights are given of 6-OHDA-induced effects on striatal mAchR and nAch R densities, and partly explains the therapeutic effect of BoNT-A in hemi-PD rats on a cellular level. Expand
BRET- and fluorescence anisotropy-based assays for real-time monitoring of ligand binding to M2 muscarinic acetylcholine receptors.
TLDR
It is shown that BRET- and FA-based binding assays represent valuable alternatives to radioactivity-based methods for screening purposes and for a precise characterization of binding kinetics supporting the exploration of binding mechanisms. Expand
Novel long‐acting antagonists of muscarinic ACh receptors
TLDR
The aim of this study was to develop potent and long‐acting antagonists of muscarinic ACh receptors by synthesizing and testing 4‐hexyloxy and 4‐butyloxy derivatives of 1‐[2‐(4‐oxidobenzoyloxy)ethyl]‐1,2,3,6‐tetrahydropyridin‐1‐ium. Expand

References

SHOWING 1-10 OF 39 REFERENCES
Molecular Mechanisms of Methoctramine Binding and Selectivity at Muscarinic Acetylcholine Receptors
TLDR
The hypothesis that methoctramine high-affinity binding to the M2 receptors involves simultaneous interaction with both the orthosteric binding site and the allostericbinding site located between the second and third extracellular loops is confirmed. Expand
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.
TLDR
Two amino acids account entirely for the (approximately 100-fold) M2/M5 selectivity of the alkane-bisammonium and the caracurine V type allosteric ligands at NMS-free M2 receptors. Expand
Binding of Orthosteric Ligands to the Allosteric Site of the M2 Muscarinic Cholinergic Receptor
TLDR
Monomers of the hemagglutinin (HA)- and FLAG-tagged human M2 receptor have been purified from coinfected Sf9 cells and examined for any effect of the antagonist N-methyl scopolamine or the agonist oxotremorine-M on the rate at which N-[3H]methyl scopamine dissociates from the orthosteric site (kobsd). Expand
Identification of Orthosteric and Allosteric Site Mutations in M2 Muscarinic Acetylcholine Receptors That Contribute to Ligand-selective Signaling Bias*
TLDR
Molecular modeling of 77-LH-28-1 and N-desmethylclozapine yielded novel binding poses consistent with the possibility that the functional selectivity of such agents may arise from a bitopic mechanism, and evidence for the existence of pathway-specific receptor conformations is provided. Expand
Structure of the human M2 muscarinic acetylcholine receptor bound to an antagonist
TLDR
The structure of the antagonist-bound human M2 receptor is reported, the first human acetylcholine receptor to be characterized structurally, to the authors' knowledge, and provides insights into the challenges of developing subtype-selective ligands for muscarinic receptors and their propensity for allosteric regulation. Expand
Role of acidic amino acids in the allosteric modulation by gallamine of antagonist binding at the m2 muscarinic acetylcholine receptor.
TLDR
The results suggest that the allosteric site for gallamine binding in the m2 receptor residues at or near the putative third outer domain and that both the EDGE motif and Asp-97 play an essential role in the interaction between the two sites. Expand
Molecular Mechanisms of Bitopic Ligand Engagement with the M1 Muscarinic Acetylcholine Receptor*
TLDR
Findings provide valuable structural and mechanistic insights into bitopic ligand actions and receptor activation and support a role for ECL2 in dictating the active states that can be adopted by a G protein-coupled receptor. Expand
Activation and allosteric modulation of a muscarinic acetylcholine receptor
TLDR
The structure of an agonist-bound, active state of the human M2 muscarinic acetylcholine receptor stabilized by a G-protein mimetic camelid antibody fragment isolated by conformational selection using yeast surface display reveals larger conformational changes in the extracellular region and orthosteric binding site than observed in the active states of the β2AR and rhodopsin. Expand
Crystal structures of the M1 and M4 muscarinic acetylcholine receptors
TLDR
Comparison of crystal structures of the M1 and M4 muscarinic receptors bound to the inverse agonist, tiotropium, reveals differences in the orthosteric and allosteric binding sites that contribute to a role in drug selectivity at this important receptor family. Expand
Structural basis for modulation of a G-protein-coupled receptor by allosteric drugs
TLDR
Simulations revealed mechanisms that contribute to positive and negative allosteric modulation of classical ligand binding, including coupled conformational changes of the two binding sites and electrostatic interactions between ligands in these sites, which provide a structural basis for the rational design of allosterics modulators targeting muscarinic and possibly other GPCRs. Expand
...
1
2
3
4
...