Structural highlights
Publication Abstract from PubMed
Duramycin is a heavily post-translationally modified peptide that binds phosphatidylethanolamine. It has been investigated as an antibiotic, an inhibitor of viral entry, a therapeutic for cystic fibrosis, and a tumor and vasculature imaging agent. Duramycin contains a beta-hydroxylated Asp (Hya) and four macrocycles, including an essential lysinoalanine (Lal) cross-link. The mechanism of Lal formation is not known. Here we show that Lal is installed stereospecifically by DurN via addition of Lys19 to a dehydroalanine. The structure of DurN reveals an unusual dimer with a new fold. Surprisingly, in the structure of duramycin bound to DurN, no residues of the enzyme are near the Lal cross-link. Instead, Hya15 of the substrate makes interactions with Lal, suggesting it acts as a base to deprotonate Lys19 during catalysis. Biochemical data suggest that DurN preorganizes the reactive conformation of the substrate, such that the Hya15 of the substrate can serve as the catalytic base for Lal formation.
Substrate-assisted enzymatic formation of lysinoalanine in duramycin.,An L, Cogan DP, Navo CD, Jimenez-Oses G, Nair SK, van der Donk WA Nat Chem Biol. 2018 Oct;14(10):928-933. doi: 10.1038/s41589-018-0122-4. Epub 2018, Sep 3. PMID:30177849[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ An L, Cogan DP, Navo CD, Jimenez-Oses G, Nair SK, van der Donk WA. Substrate-assisted enzymatic formation of lysinoalanine in duramycin. Nat Chem Biol. 2018 Oct;14(10):928-933. doi: 10.1038/s41589-018-0122-4. Epub 2018, Sep 3. PMID:30177849 doi:http://dx.doi.org/10.1038/s41589-018-0122-4
