title: Target Elucidation by Cocrystal Structures of NADH-Ubiquinone Oxidoreductase of Plasmodium falciparum (PfNDH2) with Small Molecule To Eliminate Drug-Resistant Malaria.
abstract: Drug-resistant malarial strains have been continuously emerging recently, which posts a great challenge for the global health. Therefore, new antimalarial drugs with novel targeting mechanisms are urgently needed for fighting drug-resistant malaria. NADH-ubiquinone oxidoreductase of Plasmodium falciparum (PfNDH2) represents a viable target for antimalarial drug development. However, the absence of structural information on PfNDH2 limited rational drug design and further development. Herein, we report high resolution crystal structures of the PfNDH2 protein for the first time in Apo-, NADH-, and RYL-552 (a new inhibitor)-bound states. The PfNDH2 inhibitor exhibits excellent potency against both drug-resistant strains in vitro and parasite-infected mice in vivo via a potential allosteric mechanism. Furthermore, it was found that the inhibitor can be used in combination with dihydroartemisinin (DHA) synergistically. These findings not only are important for malarial PfNDH2 protein-based drug development but could also have broad implications for other NDH2-containing pathogenic microorganisms such as Mycobacterium tuberculosis.
authors.affiliation: MOE Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, Tsinghua University , Beijing 100084, China.|MOE Key Laboratory of Protein Sciences, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University , Beijing 100084, China.
authors.forename: Yiqing
authors.identifier: 0000-0002-6522-6209
authors.initials: Y
authors.lastname: Yang
authors.affiliation: MOE Key Laboratory of Protein Sciences, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University , Beijing 100084, China.
authors.forename: You
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Biochemistry and Molecular Biology, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Peking Union Medical College , Beijing 100005, China.
authors.forename: Xiaolu
authors.initials: X
authors.lastname: Li
authors.affiliation: MOE Key Laboratory of Protein Sciences, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University , Beijing 100084, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: MOE Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, Tsinghua University , Beijing 100084, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wu
authors.affiliation: MOE Key Laboratory of Protein Sciences, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University , Beijing 100084, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Yu
authors.affiliation: MOE Key Laboratory of Protein Sciences, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University , Beijing 100084, China.
authors.forename: Jingpeng
authors.initials: J
authors.lastname: Ge
authors.affiliation: Institut Pasteur of Shanghai, CAS Key Laboratory of Molecular Virology and Immunology, Chinese Academy of Sciences , Shanghai 200031, China.
authors.forename: Zhenghui
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Institut Pasteur of Shanghai, CAS Key Laboratory of Molecular Virology and Immunology, Chinese Academy of Sciences , Shanghai 200031, China.
authors.forename: Lubin
authors.initials: L
authors.lastname: Jiang
authors.affiliation: MOE Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, Tsinghua University , Beijing 100084, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Rao
authors.affiliation: MOE Key Laboratory of Protein Sciences, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University , Beijing 100084, China.
authors.forename: Maojun
authors.initials: M
authors.lastname: Yang
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D004351:Drug Resistance; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors* / Q000737:chemistry; D016778:Malaria, Falciparum / Q000517:prevention & control*; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology; D011487:Protein Conformation
chemical_list: D042967:Electron Transport Complex I