Role of dynamic cooperativity in the mechanism of hexameric M17 aminopeptidases.

M17 aminopeptidases possess a conserved hexameric arrangement throughout all kingdoms of life. Of particular interest is the M17 from Plasmodium falciparum (PfA-M17), which is a validated antimalarial drug target. Herein we have examined PfA-M17 using an integrated structural biology and biochemical approach to provide the first description of the fundamental role of oligomerisation. We found that, rather than operating as discrete units, the active sites of the PfA-M17 hexamer are linked by a dynamic loop, which operates cooperatively to regulate activity. Further, we characterised motions in key surface loops that moderate access to the central catalytic cavity. Based on our new understanding of the dynamics inherent to PfA-M17, we propose a novel mechanism that would allow exquisite control of enzyme function in response to cellular signals, and go on to discuss how, through divergent evolution, this mechanism might have developed to moderate key differences in M17 function across species.