| Autor: |
Puskar NL; Division of Chemistry and Chemical Engineering, California Institute of Technology, 164-30, Pasadena, CA 91125, USA., Lester HA, Dougherty DA |
| Jazyk: |
angličtina |
| Zdroj: |
ACS chemical biology [ACS Chem Biol] 2012 May 18; Vol. 7 (5), pp. 841-6. Date of Electronic Publication: 2012 Feb 14. |
| DOI: |
10.1021/cb200448j |
| Abstrakt: |
The nicotinic acetylcholine receptors (nAChRs) are a family of closely related but pharmacologically distinct neurotransmitter-gated ion channels. They are therapeutic targets for a wide range of neurological disorders, and a key issue in drug development is selective targeting among the more than 20 subtypes of nAChRs that are known. The present work evaluates a proposed hydrogen bonding interaction involving a residue known as the "loop B glycine" that distinguishes receptors that are highly responsive to ACh and nicotine from those that are much less so. We have performed structure-function studies on the loop B site, including unnatural amino acid mutagenesis, in three different nAChR subtypes and found that the correlation between agonist potency and this residue is strong. Low potency receptor subtypes have a glycine at this key site, and mutation to a residue with a side chain converts a low potency receptor to a high potency receptor. Innately high potency receptors have a lysine at the loop B site and show a decrease in potency for the reverse mutation (i.e., introducing a glycine). This residue lies outside of the agonist binding site, and studies of other residues at the agonist binding site show that the details of how changes at the loop B glycine site impact agonist potency vary for differing receptor subtypes. This suggests a model in which the loop B residue influences the global shape of the agonist binding site rather than modulating any specific interaction. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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