5ZIT

Crystal structure of human Enterovirus D68 RdRp in complex with NADPH

5ZIT の概要

• エントリーDOI: 10.2210/pdb5zit/pdb
• 分子名称: RdRp, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, DI(HYDROXYETHYL)ETHER, ... (4 entities in total)
• 機能のキーワード: evd68-rdrp, complex, inhibitor, nadph-na4, structure-based design, rna binding protein
• 由来する生物種: Enterovirus D68
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 52764.80

構造登録者

Wang, M.L.,Li, L.,Chen, Y.P.,Jiang, H.,Zhang, Y.,Su, D. (登録日: 2018-03-17, 公開日: 2019-04-17, 最終更新日: 2023-11-22)

主引用文献

Li, L.,Wang, M.,Chen, Y.,Hu, T.,Yang, Y.,Zhang, Y.,Bi, G.,Wang, W.,Liu, E.,Han, J.,Lu, T.,Su, D.
Structure of the enterovirus D68 RNA-dependent RNA polymerase in complex with NADPH implicates an inhibitor binding site in the RNA template tunnel.
J.Struct.Biol., :107510-107510, 2020

PubMed Abstract: Enterovirus D68 (EV-D68) is an emerging viral pathogen belonging to the Enterovirus genus of the Picornaviridae family, which is a serious threat to human health and has resulted in significant economic losses. The EV-D68 genome encodes an RNA-dependent RNA polymerase (RdRp) 3D, which is central for viral genome replication and considered as a promising target for specific antiviral therapeutics. In this study, we report the crystal structures of human EV-D68 RdRp in the apo state and in complex with the inhibitor NADPH, which was selected by using a structure-based virtual screening approach. The EV-D68-RdRp-NADPH complex is the first RdRp-inhibitor structure identified in the species Enterovirus D. The inhibitor NADPH occupies the RNA template binding channel of EV-D68 RdRp with a novel binding pocket. Additionally, residues involved in the NADPH binding pocket of EV-D68 RdRp are highly conserved in RdRps of enteroviruses. Therefore, the enzyme activity of three RdRps from EV-D68, poliovirus, and enterovirus A71 is shown to decrease when titrated with NADPH separately in vitro. Furthermore, we identified that NADPH plays a pivotal role as an RdRp inhibitor instead of a chain terminator during restriction of RNA-dependent RNA replication. In the future, derivatives of NADPH may pave the way for novel inhibitors of RdRp through compound modification, providing potential antiviral agents for treating enteroviral infection and related diseases.

PubMed: 32353513
DOI: 10.1016/j.jsb.2020.107510

実験手法

X-RAY DIFFRACTION (3.196 Å)