Capreomycin is a potent ribosome-targeting antibiotic that is an essential component of current antituberculosis treatments, particularly in the case of multi-drug resistant Mycobacterium tuberculosis (Mtb). Optimal capreomycin binding and Mtb ribosome inhibition requires ribosomal RNA (rRNA) methylation in both ribosome subunits by TlyA (Rv1694), an enzyme with dual 2'-O-methytransferase and putative hemolytic activities. Despite TlyA's important role in capreomycin sensitivity and identification of inactivating mutations in the corresponding Mtb gene tylA which cause resistance to capreomycin, our current structural and mechanistic understanding of TlyA action remains limited. Here, we present structural and functional analyses of Mtb TlyA interaction with its obligatory cosubstrate for methyltransferase activity, S-adenosyl-L-methionine (SAM). Despite adopting a complete Class I methyltransferase fold containing conserved SAM-binding and catalytic motifs, the isolated TlyA carboxyterminal domain (CTD) exhibits no detectable affinity for SAM. Further analyses identify a tetrapeptide motif (RxWV) in the TlyA interdomain linker as indispensable for cosubstrate binding. Our results also suggest that structural plasticity of the RxWV motif could contribute to TlyA domain interactions as well as specific recognition of its two structurally distinct rRNA targets. Our findings thus reveal a novel motif requirement for SAM binding by TlyA and set the stage for future mechanistic studies of TlyA substrate recognition and modification which underpin Mtb sensitivity to capreomycin.
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