AN INHIBITOR OF RIBOSOMAL PEPTIDYL TRANSFERASE USING TRANSITION-STATEANALOGY

The phosphoramidate of CCdAp and puromycin (CCdApPuro) is a potent inh ibitor of ribosomal peptidyl transferase, as assayed by the fragment r eaction. Inhibition is competitive at the ribosomal A-site. CCdApPuro protects P-site-associated bases in the peptidyl transferase loop regi on of 23S rRNA from carbodiimide modification. The K-i's of structural homologues of CCdApPuro suggest that both the CCdA and puromycin moie ties participate in binding. Thus, CCdApPuro appears to bridge the A- and P-sites of the ribosome, implying that substrates are juxtaposed w ith a geometry suitable for direct reaction during peptidyl transfer.