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1512 normal enzyme. Then, they replaced the oxygen in question with a sulfur atom. The reaction didn’t work as well because, by the rules of chemistry, sulfur doesn’t like to bind to magnesium. But sulfur does like manganese and cadmium ions. So they replaced the magnesium with one of these other metal ions and measured the reaction. The researchers saw that these other metal ions restored (or “rescued”) enzymatic activity. In short, the enzyme needs a bond where the oxygen and the magnesium are, but the bond doesn’t have to be between oxygen and magnesium. As complicated as that is, plucking out one atom and trading it for another is itself a tricky business. Because most enzymes are made of stubborn amino acids and not nucleotides, atomic mutagenesis can be diffi cult. And usually when researchers have tried atomic mutagenesis, they’ve mutated the substrate (the molecule that the reaction acts upon) instead of the enzyme (the molecule that acts). Here, Piccirilli, Herschlag, and colleagues directed the applications of atomic mutagenesis to the molecule that does the work. To test that a specifi c oxygen in the intron binds to the magnesium ion, the researchers fi rst had to compile a short list of potential atoms to which the magnesium might bind. By combining literature data from structural models and functional studies with a random sprinkling of sulfur atoms in the intron to fi nd critical oxygen contacts, Piccirilli, Herschlag, and colleagues established a group of specifi c oxygen atoms to watch. They tried the metal rescue experiment with each of these oxygens, and the only enzyme rescued by the metal switch was the one in which they changed the C262 oxygen to a sulfur. Therefore, they concluded that this specifi c oxygen atom makes a critical contact with the magnesium ion. The strategy of atomic mutagenesis combined with metal ion rescue can be used to help understand the mechanism of other RNA and protein metalloenzymes.