The structural basis of ribosome activity in peptide bond synthesis

Using the atomic structures of the large ribosomal subunit from Haloarcula marismortui and its complexes with two substrate analogs, we establish that the ribosome is a ribozyme and address the catalytic properties of its all -RNA active site. Both substrate analogs are contacted exclusively by conse rved ribosomal RNA (rRNA) residues from domain V of 23S rRNA; there are no protein side-chain atoms closer than about 18 angstroms to the peptide bond being synthesized. The mechanism of peptide band synthesis appears to rese mble the reverse of the acylation step in serine proteases, with the base o f A2486 (A2451 in Escherichia coti) playing the same general base role as h istidine-57 in chymotrypsin. The unusual pK(a) (where K-a is the acid disso ciation constant) required for A2486 to perform this function may derive in part from its hydrogen bonding to G2482 (G2447 in E. coli), which also int eracts with a buried phosphate that could stabilize unusual tautomers of th ese two bases. The polypeptide exit tunnel is largely formed by RNA but has significant contributions from proteins L4, L22, and L39e, and its exit is encircled by proteins L19, L22, L23, L24, L29, and L31e.