MF7001004 Lysinoalanine synthase, DurN 6c0g X-ray 2.15 Homodimer Streptomyces cinnamoneus 30177849 An L, Cogan DP, Navo CD, Jiménez-Osés G, Nair SK, van der Donk WA Nat. Chem. Biol. 2018 10 14 928-933 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 β-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. 2 1 Homooligomeric enzymes Homodimeric enzymes All chains according to the most probable oligomerization state stored in PDBe were considered. A Lysinoalanine synthase Streptomyces cinnamoneus A0A3F2YLX1 8 121 94% SGMKSAKEPTIYQDVDIIRRIQELMVLCSLLPPDGKLREALELALALHEEPALARITPLTNLHPFATKAWLETLWLGEGVSSEEKELVAWQNKSENMGPAIRELKNAEQQSGITLVARLTS 121 secondary structure helix 14 30 secondary structure helix 35 47 secondary structure helix 48 56 secondary structure helix 63 77 secondary structure helix 81 91 secondary structure helix 93 112 pfam PF19375 DurN substrate-assisted peptide maturase 18 118 B-2 Lysinoalanine synthase Streptomyces cinnamoneus A0A3F2YLX1 8 121 94% SGMKSAKEPTIYQDVDIIRRIQELMVLCSLLPPDGKLREALELALALHEEPALARITPLTNLHPFATKAWLETLWLGEGVSSEEKELVAWQNKSENMGPAIRELKNAEQQSGITLVARLTS 121 pfam PF19375 DurN substrate-assisted peptide maturase 18 118 Insufficient evidence (candidate) The full structure participates in mutual synergistic folding. - The overall structure of DurN consists of an interlaced homodimer where helix α1 is engaged with residues from helices α2–α6 in the adjacent monomer. An intermolecular, antiparallel β-strand is also formed between the monomers (PMID:30177849). A N/A B-2 N/A