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Binding of N-methylscopolamine to the extracellular domain of muscarinic acetylcholine receptors
J. Jakubík, A. Randáková, P. Zimčík, EE. El-Fakahany, V. Doležal,
Jazyk angličtina Země Anglie, Velká Británie
Typ dokumentu časopisecké články, práce podpořená grantem
Free Medical Journals od 2011
Nature Open Access od 2011-12-01
PubMed Central od 2011
Europe PubMed Central od 2011
ProQuest Central od 2011-01-01
Open Access Digital Library od 2011-01-01
Open Access Digital Library od 2011-01-01
Health & Medicine (ProQuest) od 2011-01-01
ROAD: Directory of Open Access Scholarly Resources od 2011
Odkazy
PubMed
28091608
DOI
10.1038/srep40381
Knihovny.cz E-zdroje
- MeSH
- biologické modely MeSH
- CHO buňky MeSH
- Cricetulus MeSH
- kinetika MeSH
- křečci praví MeSH
- lidé MeSH
- ligandy MeSH
- mutantní proteiny chemie metabolismus MeSH
- N-methylskopolamin chemie metabolismus MeSH
- proteinové domény MeSH
- receptory muskarinové chemie metabolismus MeSH
- sekundární struktura proteinů MeSH
- simulace molekulární dynamiky MeSH
- tritium metabolismus MeSH
- vazba proteinů MeSH
- vazebná místa MeSH
- zrychlení MeSH
- zvířata MeSH
- Check Tag
- křečci praví MeSH
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
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 muscarinic acetylcholine receptors, suggesting allosteric binding. The affinity of NMS at the allosteric site is in the micromolar range for all receptor subtypes. Using molecular modelling of the M2 receptor we found that E172 and E175 in the second extracellular loop and N419 in the third extracellular loop are involved in allosteric binding of NMS. Mutation of these amino acids to alanine decreased affinity of NMS for the allosteric binding site confirming results of molecular modelling. The allosteric binding site of NMS overlaps with the binding site of some allosteric, ectopic and bitopic ligands. Understanding of interactions of NMS at the allosteric binding site is essential for correct analysis of binding and action of these ligands.
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