Structure of the Plasmodium falciparum M17 aminopeptidase and significance for the design of drugs targeting the neutral exopeptidases

Sheena McGowan, Christine A. Oellig, Woldeamanuel A. Birru, Tom T. Caradoc-Davies, Colin M. Stack, Jonathan Lowther, Tina Skinner-Adams, Artur Mucha, Pawel Kafarski, Jolanta Grembecka, Katherine R. Trenholme, Ashley M. Buckle, Donald L. Gardiner, John P. Dalton, James C. Whisstock

    Research output: Contribution to journalArticle

    Abstract

    Current therapeutics and prophylactics for malaria are under severe challenge as a result of the rapid emergence of drug-resistant parasites. The human malaria parasite Plasmodium falciparum expresses two neutral aminopeptidases, PfA-M1 and PfA-M17, which function in regulating the intracellular pool of amino acids required for growth and development inside the red blood cell. These enzymes are essential for parasite viability and are validated therapeutic targets. We previously reported the x-ray crystal structure of the monomeric PfA-M1 and proposed a mechanism for substrate entry and free amino acid release from the active site. Here, we present the x-ray crystal structure of the hexameric leucine aminopeptidase, PfA-M17, alone and in complex with two inhibitors with antimalarial activity. The six active sites of the PfA-M17 hexamer are arranged in a disc-like fashion so that they are orientated inwards to form a central catalytic cavity; flexible loops that sit at each of the six entrances to the catalytic cavern function to regulate substrate access. In stark contrast to PfA-M1, PfA-M17 has a narrow and hydrophobic primary specificity pocket which accounts for its highly restricted substrate specificity. We also explicate the essential roles for the metal-binding centers in these enzymes (two in PfA-M17 and one in PfA-M1) in both substrate and drug binding. Our detailed understanding of the PfA-M1 and PfA-M17 active sites now permits a rational approach in the development of a unique class of two-target and/or combination antimalarial therapy.
    Original languageEnglish
    Pages (from-to)2449-2454
    Number of pages5
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume107
    Issue number6
    DOIs
    Publication statusPublished - 2010

    Keywords

    • drug design
    • malaria

    Fingerprint

    Dive into the research topics of 'Structure of the Plasmodium falciparum M17 aminopeptidase and significance for the design of drugs targeting the neutral exopeptidases'. Together they form a unique fingerprint.

    Cite this