8OFW

Crystal structure of the full-length dihydroorotate dehydrogenase from Mycobacterium tuberculosis

Summary for 8OFW

• Entry DOI: 10.2210/pdb8ofw/pdb
• Descriptor: Dihydroorotate dehydrogenase (quinone), FLAVIN MONONUCLEOTIDE (2 entities in total)
• Functional Keywords: dihydroorotate dehydrogenase, flavoenzyme; pyrimidine biosynthesis, oxidoreductase
• Biological source: Mycobacterium tuberculosis
• Total number of polymer chains: 2
• Total formula weight: 81352.56

Authors

Alberti, M.,Ferraris, D.M.,Miggiano, R. (deposition date: 2023-03-17, release date: 2023-09-06)

Primary citation

Alberti, M.,Sainas, S.,Ronchi, E.,Lolli, M.L.,Boschi, D.,Rizzi, M.,Ferraris, D.M.,Miggiano, R.
Biochemical characterization of Mycobacterium tuberculosis dihydroorotate dehydrogenase and identification of a selective inhibitor.
Febs Lett., 597:2119-2132, 2023

PubMed Abstract: Mycobacterium tuberculosis (MTB) is the etiologic agent of tuberculosis (TB), an ancient disease which causes 1.5 million deaths worldwide. Dihydroorotate dehydrogenase (DHODH) is a key enzyme of the MTB de novo pyrimidine biosynthesis pathway, and it is essential for MTB growth in vitro, hence representing a promising drug target. We present: (i) the biochemical characterization of the full-length MTB DHODH, including the analysis of the kinetic parameters, and (ii) the previously unreleased crystal structure of the protein that allowed us to rationally screen our in-house chemical library and identify the first selective inhibitor of mycobacterial DHODH. The inhibitor has fluorescence properties, potentially instrumental to in cellulo imaging studies, and exhibits an IC value of 43 μm, paving the way to hit-to-lead process.

PubMed: 37278160
DOI: 10.1002/1873-3468.14680

Experimental method

X-RAY DIFFRACTION (3.8 Å)