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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...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2014
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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. |
format | Online Article Text |
id | pubmed-4138238 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
record_format | MEDLINE/PubMed |
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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