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Structural basis for the function and inhibition of dihydroorotate dehydrogenase from Schistosoma mansoni
Author(s) -
Mori Renan M.,
Aleixo Mariana A. A.,
Zapata Luana C. C.,
Calil Felipe A.,
Emery Flávio S.,
ato M. Cristina
Publication year - 2021
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.15367
Subject(s) - dihydroorotate dehydrogenase , drug discovery , biochemistry , druggability , biology , oxidoreductase , avermectin , chemistry , stereochemistry , pharmacology , computational biology , enzyme , gene , anatomy
Schistosomiasis is a serious public health problem, prevalent in tropical and subtropical areas, especially in poor communities without access to safe drinking water and adequate sanitation. Transmission has been reported in 78 countries, and its control depends on a single drug, praziquantel, which has been used over the past 30 years. Our work is focused on exploiting target‐based drug discovery strategies to develop new therapeutics to treat schistosomiasis. In particular, we are interested in evaluating the enzyme dihydroorotate dehydrogenase (DHODH) as a drug target. DHODH is a flavoenzyme that catalyzes the stereospecific oxidation of ( S )‐dihydroorotate (DHO) to orotate during the fourth and only redox step of the de novo pyrimidine nucleotide biosynthetic pathway. Previously, we identified atovaquone, used in the treatment of malaria, and its analogues, as potent and selective inhibitors against Schistosoma mansoni DHODH ( SmDHODH ). In the present article, we report the first crystal structure of SmDHODH in complex with the atovaquone analogue inhibitor 2‐((4‐fluorophenyl)amino)‐3‐hydroxynaphthalene‐1,4‐dione (QLA). We discuss three major findings: (a) the open conformation of the active site loop and the unveiling of a novel transient druggable pocket for class 2 DHODHs; (b) the presence of a protuberant domain, only present in Schistosoma spp DHODHs, that was found to control and modulate the dynamics of the inhibitor binding site; (c) a detailed description of an unexpected binding mode for the atovaquone analogue to Sm DHODH. Our findings contribute to the understanding of the catalytic mechanism performed by class 2 DHODHs and provide the molecular basis for structure‐guided design of Sm DHODH inhibitors. Database The structural data are available in Protein Data Bank (PDB) database under the accession code number 6UY4 .