CaltechAUTHORS
  A Caltech Library Service

Probing the Effects of Residues Located Outside the Agonist Binding Site on Drug-Receptor Selectivity in the Nicotinic Receptor

Puskar, Nyssa L. and Lester, Henry A. and Dougherty, Dennis A. (2012) Probing the Effects of Residues Located Outside the Agonist Binding Site on Drug-Receptor Selectivity in the Nicotinic Receptor. ACS Chemical Biology, 7 (5). pp. 841-846. ISSN 1554-8929. PMCID PMC3356501. doi:10.1021/cb200448j. https://resolver.caltech.edu/CaltechAUTHORS:20120613-133532352

[img] PDF - Accepted Version
See Usage Policy.

1MB
[img]
Preview
PDF - Supplemental Material
See Usage Policy.

260kB

Use this Persistent URL to link to this item: https://resolver.caltech.edu/CaltechAUTHORS:20120613-133532352

Abstract

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.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1021/cb200448jDOIArticle
http://pubs.acs.org/doi/abs/10.1021/cb200448jPublisherArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3356501/PubMed CentralArticle
ORCID:
AuthorORCID
Lester, Henry A.0000-0002-5470-5255
Dougherty, Dennis A.0000-0003-1464-2461
Additional Information:© 2012 American Chemical Society. Published In Issue May 18, 2012; Article ASAP: February 14, 2012; Just Accepted Manuscript: February 01, 2012; Received: October 31, 2011; Accepted: February 01, 2012. This work was supported by the National Institutes of Health (NS 34407 and NS 11756). We also thank a referee for pointing out the sequence differences between the Limanea and Aplysia forms of AChBP.
Funders:
Funding AgencyGrant Number
NIHNS 34407
NIHNS 11756
Issue or Number:5
PubMed Central ID:PMC3356501
DOI:10.1021/cb200448j
Record Number:CaltechAUTHORS:20120613-133532352
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20120613-133532352
Official Citation:Probing the Effects of Residues Located Outside the Agonist Binding Site on Drug-Receptor Selectivity in the Nicotinic Receptor Nyssa L. Puskar, Henry A. Lester, and Dennis A. Dougherty ACS Chemical Biology 2012 7 (5), 841-846
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:31897
Collection:CaltechAUTHORS
Deposited By: Jason Perez
Deposited On:13 Jun 2012 21:44
Last Modified:09 Nov 2021 20:02

Repository Staff Only: item control page