The highly persistent and often lethal human pathogen, Mycobacterium tuberculosis contains at least 88 toxin -antitoxin (TA) genes. More than half of these encode VapC PIN domain endoribonucleases that inhibit cell growth by unknown mechanisms. Here we show that VapC20 of M. tuberculosis inhibits translation by cleavage of the Sarcin Ricin Loop (SRL) of 23S rRNA, at the same position where Sarcin and other eukaryotic ribo-toxins cleave. Toxin-inhibited cells can be rescued by expression of the

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... ntitoxin, thereby raising the possibility that vapC20 contributes to the extreme persistence exhibited by M. tuberculosis. VapC20 cleavage is inhibited by mutations in the SRL that flank the cleavagesite but not by changes elsewhere in the loop. Disruption of the SRL stem abolishes cleavage; however, further mutations that restore the SRL stem structure restore cleavage, revealing that the structure rather than the exact sequence of the SRL is important for this activity.