CaltechAUTHORS
  A Caltech Library Service

An Unaltered Orthosteric Site and a Network of Long-Range Allosteric Interactions for PNU-120596 in α7 Nicotinic Acetylcholine Receptors

Marotta, Christopher B. and Lester, Henry A. and Dougherty, Dennis A. (2015) An Unaltered Orthosteric Site and a Network of Long-Range Allosteric Interactions for PNU-120596 in α7 Nicotinic Acetylcholine Receptors. Chemistry and Biology, 22 (8). pp. 1063-1073. ISSN 1074-5521. PMCID PMC4547686. doi:10.1016/j.chembiol.2015.06.018. https://resolver.caltech.edu/CaltechAUTHORS:20150728-085848506

[img] PDF - Accepted Version
See Usage Policy.

1MB
[img] PDF (Figure S1) - Supplemental Material
See Usage Policy.

158kB

Use this Persistent URL to link to this item: https://resolver.caltech.edu/CaltechAUTHORS:20150728-085848506

Abstract

Nicotinic acetylcholine receptors (nAChRs) are vital to neuronal signaling, are implicated in important processes such as learning and memory, and are therapeutic targets for neural diseases. The α7 nAChR has been implicated in Alzheimer's disease and schizophrenia, and allosteric modulators have become one focus of drug development efforts. We investigate the mode of action of the α7-selective positive allosteric modulator, PNU-120596, and show that the higher potency of acetylcholine in the presence of PNU-120596 is not due to an altered agonist binding site. In addition, we propose several residues in the gating interface and transmembrane region that are functionally important to transduction of allosteric properties, and link PNU-120596, the acetylcholine binding region, and the receptor gate. These results suggest global protein stabilization from a communication network through several key residues that alter the gating equilibrium of the receptor while leaving the agonist binding properties unperturbed.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1016/j.chembiol.2015.06.018DOIArticle
http://www.sciencedirect.com/science/article/pii/S1074552115002446PublisherArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4547686PubMed CentralArticle
ORCID:
AuthorORCID
Lester, Henry A.0000-0002-5470-5255
Dougherty, Dennis A.0000-0003-1464-2461
Additional Information:© 2015 Elsevier Ltd. Received: January 22, 2015; Revised: May 19, 2015; Accepted: June 10, 2015; Published: July 23, 2015. We thank Matt Rienzo and Noah Duffy for their work in making the dCA-coupled fluorinated-OMe-tyrosines and tRNA, and Emily Blythe for developing the a7 homology model. Support for this work came from the NIH (NS 34407).
Funders:
Funding AgencyGrant Number
NIHNS 34407
Issue or Number:8
PubMed Central ID:PMC4547686
DOI:10.1016/j.chembiol.2015.06.018
Record Number:CaltechAUTHORS:20150728-085848506
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20150728-085848506
Official Citation:Christopher B. Marotta, Henry A. Lester, Dennis A. Dougherty, An Unaltered Orthosteric Site and a Network of Long-Range Allosteric Interactions for PNU-120596 in α7 Nicotinic Acetylcholine Receptors, Chemistry & Biology, Volume 22, Issue 8, 20 August 2015, Pages 1063-1073, ISSN 1074-5521, http://dx.doi.org/10.1016/j.chembiol.2015.06.018. (http://www.sciencedirect.com/science/article/pii/S1074552115002446)
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:59025
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:28 Jul 2015 16:29
Last Modified:10 Nov 2021 22:13

Repository Staff Only: item control page