Significance The catalytic cycle of many enzymes often requires that several, spatially remote enzyme structural elements undergo functionally important conformational changes. To maximize and regulate the efficiency of catalysis, therefore, considerable evidence suggests that small protein enzymes can coordinate the conformational changes of multiple structural elements. Whether and how larger, multicomponent biomolecular machines such as the ribosome also exhibit such coordination, however, remains unknown. Here, we demonstrate that the ribosome coordinates multiple, functionally important conformational changes to maximize and regulate the efficiency with which it translocates along its messenger RNA template. Our findings suggest that such coordination is likely to be a general and important mechanism through which all biomolecular machines maximize and regulate their functional efficiencies.