Role of dynamic cooperativity in the mechanism of the Plasmodium falciparum M17 aminopeptidase
- Biomedicine Discovery Institute, Department of Microbiology, Monash University, Clayton Melbourne, VIC 3800, Australia.
- Biomedicine Discovery Institute, Department of Biochemistry, Monash University, Clayton Melbourne, VIC 3800, Australia.
The family of hexameric M17 aminopeptidases are conserved throughout all kingdoms of life, and are exciting drug targets for novel antimalarial and antibacterial agents. The M17 from P. falciparum (Pf-M17) is crucial to parasite survival, and a validated antimalarial drug target. We were interested to probe the role the conserved hexameric assembly plays in the function of Pf-M17, and to investigate the inherent dynamics of Pf-M17 and how they contribute to function. Towards this end, we undertook a comprehensive strategy composed of molecular dynamics simulations, X-ray crystallography, and mutational analyses to characterise the range of protein motions that Pf-M17 undergoes, and to probe the specific contribution of these motions to enzyme function. Based on these results, we propose a novel model for how Pf-M17 functions on an atomic level, whereby the two trimers within the hexamer operate in a mutually exclusive manner, and rely on a dynamic re-arrangement of bound metal ions and flexibility of a key regulatory loop. The regulatory loop possesses different characteristics in M17 aminopeptidases from other organisms, suggesting that the loop has undergone divergent evolution, and further, might be crucial to the emergence of new functions within this large and important enzyme family.