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Comprehensive Analysis of Loops at Protein-Protein Interfaces for Macrocycle Design

Inhibiting protein-protein interactions (PPIs) with synthetic molecules remains a frontier of chemical biology. Many PPIs have been successfully targeted by mimicking α-helices at interfaces, but most PPIs are mediated by non-helical, non-strand peptide loops. We sought to comprehensively identify a...

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Autores principales: Gavenonis, Jason, Sheneman, Bradley A., Siegert, Timothy R., Eshelman, Matthew R., Kritzer, Joshua A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4138238/
https://www.ncbi.nlm.nih.gov/pubmed/25038791
http://dx.doi.org/10.1038/nchembio.1580
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author Gavenonis, Jason
Sheneman, Bradley A.
Siegert, Timothy R.
Eshelman, Matthew R.
Kritzer, Joshua A.
author_facet Gavenonis, Jason
Sheneman, Bradley A.
Siegert, Timothy R.
Eshelman, Matthew R.
Kritzer, Joshua A.
author_sort Gavenonis, Jason
collection PubMed
description Inhibiting protein-protein interactions (PPIs) with synthetic molecules remains a frontier of chemical biology. Many PPIs have been successfully targeted by mimicking α-helices at interfaces, but most PPIs are mediated by non-helical, non-strand peptide loops. We sought to comprehensively identify and analyze these loop-mediated PPIs by writing and implementing LoopFinder, a customizable program that can identify loop-mediated PPIs within all protein-protein complexes in the Protein Data Bank. Comprehensive analysis of the entire set of 25,005 interface loops revealed common structural motifs and unique features that distinguish loop-mediated PPIs from other PPIs. “Hot loops,” named in analogy to protein hot spots, were identified as loops with favorable properties for mimicry using synthetic molecules. The hot loops and their binding partners represent new and promising PPIs for the development of macrocycle and constrained peptide inhibitors.
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spelling pubmed-41382382015-03-01 Comprehensive Analysis of Loops at Protein-Protein Interfaces for Macrocycle Design Gavenonis, Jason Sheneman, Bradley A. Siegert, Timothy R. Eshelman, Matthew R. Kritzer, Joshua A. Nat Chem Biol Article Inhibiting protein-protein interactions (PPIs) with synthetic molecules remains a frontier of chemical biology. Many PPIs have been successfully targeted by mimicking α-helices at interfaces, but most PPIs are mediated by non-helical, non-strand peptide loops. We sought to comprehensively identify and analyze these loop-mediated PPIs by writing and implementing LoopFinder, a customizable program that can identify loop-mediated PPIs within all protein-protein complexes in the Protein Data Bank. Comprehensive analysis of the entire set of 25,005 interface loops revealed common structural motifs and unique features that distinguish loop-mediated PPIs from other PPIs. “Hot loops,” named in analogy to protein hot spots, were identified as loops with favorable properties for mimicry using synthetic molecules. The hot loops and their binding partners represent new and promising PPIs for the development of macrocycle and constrained peptide inhibitors. 2014-07-20 2014-09 /pmc/articles/PMC4138238/ /pubmed/25038791 http://dx.doi.org/10.1038/nchembio.1580 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Gavenonis, Jason
Sheneman, Bradley A.
Siegert, Timothy R.
Eshelman, Matthew R.
Kritzer, Joshua A.
Comprehensive Analysis of Loops at Protein-Protein Interfaces for Macrocycle Design
title Comprehensive Analysis of Loops at Protein-Protein Interfaces for Macrocycle Design
title_full Comprehensive Analysis of Loops at Protein-Protein Interfaces for Macrocycle Design
title_fullStr Comprehensive Analysis of Loops at Protein-Protein Interfaces for Macrocycle Design
title_full_unstemmed Comprehensive Analysis of Loops at Protein-Protein Interfaces for Macrocycle Design
title_short Comprehensive Analysis of Loops at Protein-Protein Interfaces for Macrocycle Design
title_sort comprehensive analysis of loops at protein-protein interfaces for macrocycle design
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4138238/
https://www.ncbi.nlm.nih.gov/pubmed/25038791
http://dx.doi.org/10.1038/nchembio.1580
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