Journal
ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY
Volume 70, Issue -, Pages 1442-1452Publisher
INT UNION CRYSTALLOGRAPHY
DOI: 10.1107/S1399004714004398
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Funding
- Deutsche Forschungsgemeinschaft [ES152/4]
- DFG-Graduiertenkolleg 'Protein function at the atomic level' (SAS)
- LOEWE Research Centre of Synthetic Microbiology
- BMBF [05ES3XBA/S]
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Tyrocidine, a macrocyclic decapeptide from Bacillus brevis, is nonribosomally assembled by a set of multimodular peptide synthetases, which condense two D-amino acids and eight l-amino acids to produce this membrane-disturbing antibiotic. D-Phenylalanine, the first amino acid incorporated into tyrocidine, is catalytically derived from enzyme-bound l-Phe by the C-terminal epimerization (E) domain of tyrocidine synthetase A (TycA). The 1.5 angstrom resolution structure of the cofactor-independent TycA E domain reveals an intimate relationship to the condensation (C) domains of peptide synthetases. In contrast to the latter, the TycA E domain uses an enlarged bridge region to plug the active-site canyon from the acceptor side, whereas at the donor side a latch-like floor loop is suitably extended to accommodate the alpha III helix of the preceding peptide-carrier domain. Additionally, E domains exclusively harbour a conserved glutamate residue, Glu882, that is opposite the active-site residue His743. This active-site topology implies Glu882 as a candidate acid-base catalyst, whereas His743 stabilizes in the protonated state a transient enolate intermediate of the L <-> d isomerization.
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