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Mimicking Protein Functions with Entropically Constrained Peptides

Farrow, Blake and Wang, Andrew G. and Bunck, David N. and Heath, James R. (2016) Mimicking Protein Functions with Entropically Constrained Peptides. Biophysical Journal, 110 (3). 203A. ISSN 0006-3495. https://resolver.caltech.edu/CaltechAUTHORS:20160606-080629593

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Abstract

The biological functions of proteins, from molecular recognition to enzymatic activity, depend on the thermodynamic stability of a conformationally constrained folded structure which positions a small number of amino acid residues in an appropriate position and orientation to carry out their intended function. Most proteins use many weak interactions along a long polypeptide chain to pay the entropic penalty of occupying the native state, though there are examples in biology of short polypeptides which use a few strong or covalent interactions to stabilize a rigid structure. We have developed a completely synthetic high throughput screening platform capable of identifying conformationally constrained macrocyclic peptides with a defined biological function. Proximity-catalyzed in situ click enables discovery of short constrained peptides capable of binding to a chosen site on a protein surface with no requirements for binding pockets or naturally addressable residues in a manner analogous to monoclonal antibodies. We have successfully targeted post-translational modifications, single amino acid mutations and allosteric sites which have revealed new avenues for drug discovery. Recently, discovery of constrained peptides capable of mimicking biological activity on small molecule targets is made possible through the use of suicide substrate activity-based probes. Short constrained peptide motifs capable of activating natural residues and cofactor mimics for nucleophilic attack and decarboxylation have been identified.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1016/j.bpj.2015.11.1134DOIArticle
http://www.sciencedirect.com/science/article/pii/S0006349515023176PublisherArticle
ORCID:
AuthorORCID
Bunck, David N.0000-0002-6246-9846
Heath, James R.0000-0001-5356-4385
Additional Information:© 2016 Biophysical Society. Published by Elsevier Inc.
Issue or Number:3
Record Number:CaltechAUTHORS:20160606-080629593
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20160606-080629593
Official Citation:Blake Farrow, Andrew G. Wang, David N. Bunck, James R. Heath, Mimicking Protein Functions with Entropically Constrained Peptides, Biophysical Journal, Volume 110, Issue 3, Supplement 1, 16 February 2016, Page 203a, ISSN 0006-3495, http://dx.doi.org/10.1016/j.bpj.2015.11.1134. (http://www.sciencedirect.com/science/article/pii/S0006349515023176)
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:67673
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:06 Jun 2016 16:37
Last Modified:09 Mar 2020 13:18

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