Comprehensive Analysis of Loops at Protein-Protein Interfaces for Macrocycle Design
By Jason Gavenonis, Bradley Sheneman, Timothy R. Siegert, M. R. Eshelman, Joshua A. Kritzer. 2014
159 citations recorded by the source corpus.
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.
Subfields: Molecular Biology, Pharmacology
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In Molecular Biology
- David Baker
- Jeffrey J. Gray
- Tanja Kortemme
- Xingjie Pan
- Jens Meiler
- Frank DiMaio
- Rhiju Das
- Brian D. Weitzner
In Pharmacology
Citations in the corpus
- Macromolecular modeling and design in Rosetta: recent methods and frameworks (2020, background): “Many protein-protein interactions (PPI) are mediated by often disordered peptide segments that are responsible for most of the binding energy 112,211 – 213 .”
- Peptiderive server: derive peptide inhibitors from protein–protein interactions (2016, background): “Stabilisation of peptides by disulfide bonds has also been suggested for application to loops at interfaces (17,18).”