9EG9

Crystal structure of human dihydroorotate dehydrogenase in complex with lapachol

This is a non-PDB format compatible entry.

Summary for 9EG9

• Entry DOI: 10.2210/pdb9eg9/pdb
• Descriptor: Dihydroorotate dehydrogenase (quinone), mitochondrial, FLAVIN MONONUCLEOTIDE, OROTIC ACID, ... (8 entities in total)
• Functional Keywords: quinone, lapachol, oxidoreductase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 41421.84

Authors

Purificacao, A.D.,Benz, L.S.,Weiss, M.S.,Nonato, M.C. (deposition date: 2024-11-21, release date: 2025-08-06)

Primary citation

Purificacao, A.D.,Benz, L.S.,Lima Silva, W.J.,Emery, F.S.,Andrade, C.H.,Weiss, M.S.,Nonato, M.C.
Crystallographic Structure of Human Dihydroorotate Dehydrogenase in Complex with the Natural Product Inhibitor Lapachol.
Acs Omega, 10:29087-29097, 2025

PubMed Abstract: Dihydroorotate dehydrogenase (DHODH) is a key enzyme in the pyrimidine biosynthesis pathway, playing a critical role in cellular processes and offering therapeutic potential for antiviral, antineoplastic, and autoimmune treatments. Human DHODH (DHODH) utilizes ubiquinone as a second substrate, positioning its quinone-binding site as a promising target for inhibitor development. Lapachol, a natural naphthoquinone, has gained prominence as a valuable natural product for the discovery of novel therapeutic agents, thanks to its wide range of biological activities. In this study, we present the first crystal structure of DHODH in complex with lapachol, providing valuable insights into the interactions between this natural product and the enzyme. The structure reveals key binding interactions that mediate lapachol's affinity for DHODH and validates previously proposed computational models. Complementary molecular dynamics simulations further highlight the stability of the complex and the importance of water-mediated interactions in ligand binding. These findings enhance our understanding of how naphthoquinone derivatives, such as lapachol, interact with class 2 DHODHs, offering a foundation for the design of optimized inhibitors for therapeutic applications. By integration of structural and computational data, this study contributes to the rational design of novel DHODH inhibitors, paving the way for future exploration of lapachol and its derivatives in drug discovery.

PubMed: 40686985
DOI: 10.1021/acsomega.5c01536

Experimental method

X-RAY DIFFRACTION (1.31 Å)