title: Crystallographic and receptor binding characterization of Plasmodium falciparum macrophage migration inhibitory factor complexed to two potent inhibitors.
abstract: We report the crystal structures of two inhibitors of Plasmodium falciparum macrophage migration inhibitory factor (PfMIF) with nanomolar Ki's, analyze their interactions with the active site of PfMIF, and provide explanations regarding their selectivity of PfMIF versus human MIF. These inhibitors were also found to selectively inhibit interactions between PfMIF and the human MIF receptor CD74. The results of this study provide the framework for the development of new therapeutics that target PfMIF.
authors.affiliation: Departments of Pharmacology, ‡Internal Medicine, §Chemistry, and the ∥Yale Cancer Center, Yale University , New Haven, Connecticut 06520-8066, United States.
authors.forename: Georgios
authors.initials: G
authors.lastname: Pantouris
authors.forename: Deepa
authors.initials: D
authors.lastname: Rajasekaran
authors.forename: Alvaro
authors.initials: A
authors.lastname: Baeza Garcia
authors.forename: Victor G
authors.initials: VG
authors.lastname: Ruiz
authors.forename: Lin
authors.initials: L
authors.lastname: Leng
authors.forename: William L
authors.initials: WL
authors.lastname: Jorgensen
authors.forename: Richard
authors.initials: R
authors.lastname: Bucala
authors.forename: Elias J
authors.initials: EJ
authors.lastname: Lolis
mesh_terms: D000944:Antigens, Differentiation, B-Lymphocyte / Q000378:metabolism; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000737:chemistry / Q000378:metabolism; D008263:Macrophage Migration-Inhibitory Factors / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D055550:Protein Stability; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D000962:Antimalarials; D000949:Histocompatibility Antigens Class II; D008263:Macrophage Migration-Inhibitory Factors; D015800:Protozoan Proteins; C045084:invariant chain; C519265:macrophage-migration inhibitory factor, Plasmodium falciparum; D019746:Intramolecular Oxidoreductases; C515598:MIF protein, human