title: The X-ray structure of Plasmodium falciparum dihydroorotate dehydrogenase bound to a potent and selective N-phenylbenzamide inhibitor reveals novel binding-site interactions.
abstract: Plasmodium species are protozoan parasites that are the causative agent of malaria. Malaria is a devastating disease, and its treatment and control have been hampered by the propensity of the parasite to become drug-resistant. Dihydroorotate dehydrogenase (DHODH) has been identified as a promising new target for the development of antimalarial agents. Here, the X-ray structure of P. falciparum DHODH bound to a potent and selective N-phenylbenzamide-based inhibitor (DSM59) is described at 2.3 Å resolution. The structure elucidates novel binding-site interactions and shows how conformational flexibility of the enzyme leads to the ability to bind diverse chemical structures with high affinity. This information provides new insight into the design of high-affinity DHODH inhibitors for the treatment of malaria.
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, 6001 Forest Park Road, Dallas, TX 75390-9041, USA.
authors.forename: Xiaoyi
authors.initials: X
authors.lastname: Deng
authors.affiliation: Medicines for Malaria Venture, Geneva, Switzerland.
authors.forename: David
authors.initials: D
authors.lastname: Matthews
authors.affiliation: Departments of Chemistry and Global Health, University of Washington, Seattle, WA 98195, USA.
authors.forename: Pradipsinh K
authors.initials: PK
authors.lastname: Rathod
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, 6001 Forest Park Road, Dallas, TX 75390-9041, USA.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Phillips
mesh_terms: D001549:Benzamides / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites / Q000502:physiology; D018360:Crystallography, X-Ray; D000090722:Dihydroorotate Dehydrogenase; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000737:chemistry* / Q000378:metabolism; D010963:Plasmodium falciparum / Q000737:chemistry* / Q000201:enzymology* / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D014961:X-Ray Diffraction
chemical_list: D001549:Benzamides; D000090722:Dihydroorotate Dehydrogenase; C528506:N-(3,5-dichlorophenyl)-2-methyl-3-nitrobenzamide; D044925:Oxidoreductases Acting on CH-CH Group Donors
keywords: DSM59; Plasmodium falciparum; dihydroorotate dehydrogenase