Structure and tRNA Specificity of MibB, a Lantibiotic Dehydratase from Actinobacteria Involved in NAI-107 Biosynthesis

Manuel A. Ortega, Yue Hao, Mark C. Walker, Stefano Donadio, Margherita Sosio, Satish K. Nair, Wilfred van der Donk

Research output: Contribution to journalArticlepeer-review

Abstract

Class I lantibiotic dehydratases dehydrate selected Ser/Thr residues of a precursor peptide. Recent studies demonstrated the requirement of glutamyl-tRNAGlu for Ser/Thr activation by one of these enzymes (NisB) from the Firmicute Lactococcus lactis. However, the generality of glutamyl-tRNAGlu usage and the tRNA specificity of lantibiotic dehydratases have not been established. Here we report the 2.7-Å resolution crystal structure, along with the glutamyl-tRNAGlu utilization of MibB, a lantibiotic dehydratase from the Actinobacterium Microbispora sp. 107891 involved in the biosynthesis of the clinical candidate NAI-107. Biochemical assays revealed nucleotides A73 and U72 within the tRNAGlu acceptor stem to be important for MibB glutamyl-tRNAGlu usage. Using this knowledge, an expression system for the production of NAI-107 analogs in Escherichia coli was developed, overcoming the inability of MibB to utilize E. coli tRNAGlu. Our work provides evidence for a common tRNAGlu-dependent dehydration mechanism, paving the way for the characterization of lantibiotics from various phyla.

Original languageEnglish (US)
Pages (from-to)370-380
Number of pages11
JournalCell chemical biology
Volume23
Issue number3
DOIs
StatePublished - Mar 17 2016

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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