6MSO

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

6MSO の概要

• エントリーDOI: 10.2210/pdb6mso/pdb
• 分子名称: fumarate hydratase, IRON/SULFUR CLUSTER, GLYCEROL, ... (6 entities in total)
• 機能のキーワード: inhibitor, mitochondrial, fumarate hydratase, lyase, lyase-lyase inhibitor complex, lyase/lyase inhibitor
• 由来する生物種: Leishmania major
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 263979.52

構造登録者

Feliciano, P.R.,Drennan, C.L.,Nonato, M.C. (登録日: 2018-10-17, 公開日: 2019-01-30, 最終更新日: 2023-10-11)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.053 Å)