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Molecular Modulation of Protein Energy Landscapes

Bunck, David N. and Museth, Katrine and Atsavapranee, Beatriz and Heath, James R. (2016) Molecular Modulation of Protein Energy Landscapes. Biophysical Journal, 110 (3). 391A. ISSN 0006-3495. https://resolver.caltech.edu/CaltechAUTHORS:20160606-084658131

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Abstract

Protein catalyzed capture agents are an emerging class of oligopeptides that combine the benefits of small molecules and antibodies to furnish ligands with picomolar binding affinity, serum stability, and cell permeability. Their identification involves screening a synthetic, alkyne-functionalized epitope from a target protein against a library of cyclic peptides bearing terminal azides. We identified ligands that bind regions of superoxide dismutase 1 (SOD1), a protein that misfolds to cause amyotrophic lateral sclerosis (ALS), consistently destabilized upon mutation. Treatment of the disease is challenging because there are over 180 heritable mutations of SOD1 and virtually no well-defined binding sites addressable by traditional ligand identification strategies. These mutations ultimately cause the protein to adopt toxic conformations that aggregate and damage cellular functions within the central nervous system. PCC agents targeting regions consistently destabilized across several mutations bind and stabilize its native conformation. We characterized the impact of binding, both on the ground state stability of several mutants as well as the kinetics of SOD1 folding and denaturation.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1016/j.bpj.2015.11.2110DOIArticle
http://www.sciencedirect.com/science/article/pii/S0006349515032932PublisherArticle
ORCID:
AuthorORCID
Heath, James R.0000-0001-5356-4385
Additional Information:© 2016 Biophysical Society. Published by Elsevier Inc.
Issue or Number:3
Record Number:CaltechAUTHORS:20160606-084658131
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20160606-084658131
Official Citation:David N. Bunck, Katrine Museth, Beatriz Atsavapranee, James R. Heath, Molecular Modulation of Protein Energy Landscapes, Biophysical Journal, Volume 110, Issue 3, Supplement 1, 16 February 2016, Page 391a, ISSN 0006-3495, http://dx.doi.org/10.1016/j.bpj.2015.11.2110. (http://www.sciencedirect.com/science/article/pii/S0006349515032932)
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:67679
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:06 Jun 2016 16:27
Last Modified:03 Oct 2019 10:07

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