3I68

Plasmodium falciparum dihydroorotate dehydrogenase bound with triazolopyrimidine-based inhibitor DSM2

Summary for 3I68

• Entry DOI: 10.2210/pdb3i68/pdb
• Related: 3I65 3I68
• Descriptor: Dihydroorotate dehydrogenase homolog, mitochondrial, N-anthracen-2-yl-5-methyl[1,2,4]triazolo[1,5-a]pyrimidin-7-amine, FLAVIN MONONUCLEOTIDE, ... (5 entities in total)
• Functional Keywords: plasmodium falciparum, dihydroorotate dehydrogenase, triazolopyrimidine, inhibitor, dsm2, fad, flavoprotein, membrane, mitochondrion, mitochondrion inner membrane, oxidoreductase, pyrimidine biosynthesis, transit peptide
• Biological source: Plasmodium falciparum 3D7
• Cellular location: Mitochondrion inner membrane (By similarity); Single-pass membrane protein (Potential): Q08210
• Total number of polymer chains: 1
• Total formula weight: 47590.15

Authors

Deng, X.,Phillips, M.A. (deposition date: 2009-07-06, release date: 2009-07-28, Last modification date: 2023-09-06)

Primary citation

Deng, X.,Gujjar, R.,El Mazouni, F.,Kaminsky, W.,Malmquist, N.A.,Goldsmith, E.J.,Rathod, P.K.,Phillips, M.A.
Structural plasticity of malaria dihydroorotate dehydrogenase allows selective binding of diverse chemical scaffolds.
J.Biol.Chem., 284:26999-27009, 2009

PubMed Abstract: Malaria remains a major global health burden and current drug therapies are compromised by resistance. Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) was validated as a new drug target through the identification of potent and selective triazolopyrimidine-based DHODH inhibitors with anti-malarial activity in vivo. Here we report x-ray structure determination of PfDHODH bound to three inhibitors from this series, representing the first of the enzyme bound to malaria specific inhibitors. We demonstrate that conformational flexibility results in an unexpected binding mode identifying a new hydrophobic pocket on the enzyme. Importantly this plasticity allows PfDHODH to bind inhibitors from different chemical classes and to accommodate inhibitor modifications during lead optimization, increasing the value of PfDHODH as a drug target. A second discovery, based on small molecule crystallography, is that the triazolopyrimidines populate a resonance form that promotes charge separation. These intrinsic dipoles allow formation of energetically favorable H-bond interactions with the enzyme. The importance of delocalization to binding affinity was supported by site-directed mutagenesis and the demonstration that triazolopyrimidine analogs that lack this intrinsic dipole are inactive. Finally, the PfDHODH-triazolopyrimidine bound structures provide considerable new insight into species-selective inhibitor binding in this enzyme family. Together, these studies will directly impact efforts to exploit PfDHODH for the development of anti-malarial chemotherapy.

PubMed: 19640844
DOI: 10.1074/jbc.M109.028589

Experimental method

X-RAY DIFFRACTION (2.4 Å)