Structural highlights
FunctionPublication Abstract from PubMedLeishmaniases affect the poorest people on earth and have no effective drug therapy. Here, we present the crystal structure of the mitochondrial isoform of class I fumarate hydratase (FH) from Leishmania major and compare it to the previously determined cytosolic Leishmania major isoform. We further describe the mechanism of action of the first class-specific FH inhibitor, 2-thiomalate, through X-ray crystallography and inhibition assays. Our crystal structures of both FH isoforms with inhibitor bound at 2.05 A resolution and 1.60 A resolution show high structural similarity. These structures further reveal that the selectivity of 2-thiomalate for class I FHs is due to direct coordination of the inhibitor to the unique Fe of the catalytic [4Fe-4S] cluster that is found in class I parasitic FHs but is absent from class II human FH. These studies provide the structural scaffold in order to exploit class I FHs as potential drug targets against leishmaniases as well as Chagas diseases, sleeping sickness and malaria. Crystal structures of fumarate hydratases from Leishmania major in a complex with inhibitor 2-thiomalate.,Feliciano PR, Drennan CL, Nonato MC ACS Chem Biol. 2019 Jan 15. doi: 10.1021/acschembio.8b00972. PMID:30645090[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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