5JWC

Structure of NDH2 from plasmodium falciparum in complex with RYL-552

5JWC の概要

• エントリーDOI: 10.2210/pdb5jwc/pdb
• 関連するPDBエントリー: 5JWA 5JWB
• 分子名称: NADH dehydrogenase, putative, FLAVIN-ADENINE DINUCLEOTIDE, MAGNESIUM ION, ... (6 entities in total)
• 機能のキーワード: pfndh2, ndh2, plasmodium falciparum, malaria, inhibitor, membrane protein
• 由来する生物種: Plasmodium falciparum (isolate 3D7)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 126188.58

構造登録者

Yu, Y. (登録日: 2016-05-12, 公開日: 2017-03-22, 最終更新日: 2023-11-08)

主引用文献

Yang, Y.,Yu, Y.,Li, X.,Li, J.,Wu, Y.,Yu, J.,Ge, J.,Huang, Z.,Jiang, L.,Rao, Y.,Yang, M.
Target Elucidation by Cocrystal Structures of NADH-Ubiquinone Oxidoreductase of Plasmodium falciparum (PfNDH2) with Small Molecule To Eliminate Drug-Resistant Malaria
J. Med. Chem., 60:1994-2005, 2017

PubMed 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.

PubMed: 28195463
DOI: 10.1021/acs.jmedchem.6b01733

実験手法

X-RAY DIFFRACTION (2.051 Å)