CRYSTAL-STRUCTURE OF ERMC', AN RIBOSOMAL-RNA METHYLTRANSFERASE WHICH MEDIATES ANTIBIOTIC-RESISTANCE IN BACTERIA

The prevalent mechanism of bacterial resistance to erythromycin and ot her antibiotics of the macrolide-lincosamide-streptogramin B group (ML S) is methylation of the 23S rRNA component of the 50S subunit in bact erial ribosomes. This sequence-specific methylation is catalyzed by th e Erm group of methyltransferases (MTases). They are found in several strains of pathogenic bacteria, and ErmC is the most studied member of this class. The crystal structure of ErmC' (a naturally occurring var iant of ErmC) from Bacillus subtilis has been determined at 3.0 Angstr om resolution by multiple anomalous diffraction phasing methods. The s tructure consists of a conserved alpha/beta amino-terminal domain whic h binds the cofactor S-adenosyl-L-methionine (SAM), followed by a smal ler, alpha-helical RNA-recognition domain. The beta-sheet structure of the SAM-binding domain is well-conserved between the DNA, RNA, and sm all-molecule MTases. However, the C-terminal nucleic acid binding doma in differs from the DNA binding domains of other MTases and is unlike any previously reported RNA-recognition fold. A large, positively char ged, concave surface is found at the interface of the N- and C-termina l domains and is proposed to form part of the protein-RNA interaction surface. ErmC' exhibits the conserved structural motifs previously fou nd in the SAM-binding domain of other methyltransferases. A model of S AM bound to ErmC' is presented which is consistent with the motif cons ervation among MTases.