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Monod-Wyman-Changeux Analysis of Ligand-Gated Ion Channel Mutants

Einav, Tal and Phillips, Rob (2017) Monod-Wyman-Changeux Analysis of Ligand-Gated Ion Channel Mutants. Journal of Physical Chemistry B, 121 (15). pp. 3813-3824. ISSN 1520-6106. PMCID PMC5551692. http://resolver.caltech.edu/CaltechAUTHORS:20170131-092637914

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Abstract

We present a framework for computing the gating properties of ligand-gated ion channel mutants using the Monod-Wyman-Changeux (MWC) model of allostery. We derive simple analytic formulas for key functional properties such as the leakiness, dynamic range, half-maximal effective concentration ([EC_(50)]), and effective Hill coefficient, and explore the full spectrum of phenotypes that are accessible through mutations. Specifically, we consider mutations in the channel pore of nicotinic acetylcholine receptor (nAChR) and the ligand binding domain of a cyclic nucleotide-gated (CNG) ion channel, demonstrating how each mutation can be characterized as only affecting a subset of the biophysical parameters. In addition, we show how the unifying perspective offered by the MWC model allows us, perhaps surprisingly, to collapse the plethora of dose-response data from different classes of ion channels into a universal family of curves.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1021/acs.jpcb.6b12672DOIArticle
http://pubs.acs.org/doi/abs/10.1021/acs.jpcb.6b12672PublisherArticle
http://pubs.acs.org/doi/suppl/10.1021/acs.jpcb.6b12672PublisherSupporting Information
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5551692PubMed CentralArticle
https://arxiv.org/abs/1701.06122arXivDiscussion Paper
https://doi.org/10.1101/102194DOIDiscussion Paper
ORCID:
AuthorORCID
Einav, Tal0000-0003-0777-1193
Phillips, Rob0000-0003-3082-2809
Additional Information:© 2017 American Chemical Society. Received: December 16, 2016; Revised: January 28, 2017; Published: January 30, 2017. It is with sadness that we dedicate this paper to the memory of Klaus Schulten with whom one of us (RP) wrote his first paper in biophysics. Klaus was an extremely open and kind man, a broad and deep thinker who will be deeply missed. We thank Stephanie Barnes, Nathan Belliveau, Chico Camargo, Griffin Chure, Vahe Galstyan, Lea Goentoro, Michael Manhart, Chris Miller, Muir Morrison, Manuel Razo-Mejia, Noah Olsman, Allyson Sgro, and Jorge Zañudo for their sharp insights and valuable feedback on this work. We are also grateful to Henry Lester, Klaus Benndorf, and Vasilica Nache for helpful discussions as well as sharing their ion channel data. All plots were made in Mathematica using the CustomTicks package. This work was supported by La Fondation Pierre-Gilles de Gennes, the Rosen Center at Caltech, the National Science Foundation under NSF PHY11-25915 at the Kavli Center for Theoretical Physics, and the National Institutes of Health through DP1 OD000217 (Director’s Pioneer Award), 5R01 GM084211C, R01 GM085286, and 1R35 GM118043-01 (MIRA).
Group:Kavli Nanoscience Institute
Funders:
Funding AgencyGrant Number
La Fondation Pierre-Gilles de GennesUNSPECIFIED
CaltechUNSPECIFIED
NSFPHY11-25915
NIHDP1 OD000217
NIH5R01 GM084211C
NIHR01 GM085286
NIH1R35 GM118043-01
PubMed Central ID:PMC5551692
Record Number:CaltechAUTHORS:20170131-092637914
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20170131-092637914
Official Citation:Monod-Wyman-Changeux Analysis of Ligand-Gated Ion Channel Mutants Tal Einav and Rob Phillips The Journal of Physical Chemistry B 2017 121 (15), 3813-3824 DOI: 10.1021/acs.jpcb.6b12672
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:73863
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:31 Jan 2017 17:37
Last Modified:29 Oct 2018 15:48

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