3TQ0

Crystal structure of Leishmania major dihydroorotate dehydrogenase in complex with fumarate

Summary for 3TQ0

• Entry DOI: 10.2210/pdb3tq0/pdb
• Descriptor: Dihydroorotate dehydrogenase, FLAVIN MONONUCLEOTIDE, FUMARIC ACID, ... (7 entities in total)
• Functional Keywords: oxidoreductase
• Biological source: Leishmania major
• Total number of polymer chains: 2
• Total formula weight: 76453.41

Authors

Cordeiro, A.T.,Feliciano, P.R.,Nonato, M.C. (deposition date: 2011-09-08, release date: 2012-05-16, Last modification date: 2023-11-15)

Primary citation

Cordeiro, A.T.,Feliciano, P.R.,Pinheiro, M.P.,Nonato, M.C.
Crystal structure of dihydroorotate dehydrogenase from Leishmania major.
Biochimie, 94:1739-1748, 2012

PubMed Abstract: Dihydroorotate dehydrogenase (DHODH) is the fourth enzyme in the de novo pyrimidine biosynthetic pathway and has been exploited as the target for therapy against proliferative and parasitic diseases. In this study, we report the crystal structures of DHODH from Leishmania major, the species of Leishmania associated with zoonotic cutaneous leishmaniasis, in its apo form and in complex with orotate and fumarate molecules. Both orotate and fumarate were found to bind to the same active site and exploit similar interactions, consistent with a ping-pong mechanism described for class 1A DHODHs. Analysis of LmDHODH structures reveals that rearrangements in the conformation of the catalytic loop have direct influence on the dimeric interface. This is the first structural evidence of a relationship between the dimeric form and the catalytic mechanism. According to our analysis, the high sequence and structural similarity observed among trypanosomatid DHODH suggest that a single strategy of structure-based inhibitor design can be used to validate DHODH as a druggable target against multiple neglected tropical diseases such as Leishmaniasis, Sleeping sickness and Chagas' diseases.

PubMed: 22542640
DOI: 10.1016/j.biochi.2012.04.003

Experimental method

X-RAY DIFFRACTION (1.9 Å)