6MSN

Crystal structure of cytosolic fumarate hydratase from Leishmania major in a complex with inhibitor thiomalate

Summary for 6MSN

• Entry DOI: 10.2210/pdb6msn/pdb
• Descriptor: fumarate hydratase, IRON/SULFUR CLUSTER, (2S)-2-sulfanylbutanedioic acid, ... (4 entities in total)
• Functional Keywords: inhibitor, cytosolic, fumarate hydratase, lyase
• Biological source: Leishmania major
• Total number of polymer chains: 2
• Total formula weight: 134030.52

Authors

Feliciano, P.R.,Drennan, C.L.,Nonato, M.C. (deposition date: 2018-10-17, release date: 2019-01-30, Last modification date: 2023-10-11)

Primary citation

Feliciano, P.R.,Drennan, C.L.,Nonato, M.C.
Crystal Structures of Fumarate Hydratases from Leishmania major in a Complex with Inhibitor 2-Thiomalate.
ACS Chem. Biol., 14:266-275, 2019

PubMed Abstract: Leishmaniases 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 Å resolution and 1.60 Å 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.

PubMed: 30645090
DOI: 10.1021/acschembio.8b00972

Experimental method

X-RAY DIFFRACTION (1.591 Å)