RESEARCH ARTICLE

Structures of EV71 RNA-dependent RNA polymerase in complex with substrate and analogue provide a drug target against the hand-foot-and-mouth disease pandemic in China

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  • 1. National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; 2. Structural Biology Laboratory, Tsinghua University, Beijing 100084, China; 3. College of Life Sciences and Tianjin State Laboratory of Protein Science, Nankai University, Tianjin 300071, Chin.

Received date: 18 Apr 2010

Accepted date: 30 Apr 2010

Published date: 01 May 2010

Abstract

Enterovirus 71 (EV71), one of the major causative agents for hand-foot-and-mouth disease (HFMD), has caused more than 100 deaths among Chinese children since March 2008. The EV71 genome encodes an RNA-dependent RNA polymerase (RdRp), denoted 3Dpol, which is central for viral genome replication and is a key target for the discovery of specific antiviral therapeutics. Here we report the crystal structures of EV71 RdRp (3Dpol) and in complex with substrate guanosine-5'-triphosphate and analog 5-bromouridine-5'-triphosphate best to 2.4 ? resolution. The structure of EV71 RdRp (3Dpol) has a wider open thumb domain compared with the most closely related crystal structure of poliovirus RdRp. And the EV71 RdRp (3Dpol) complex with GTP or Br-UTP bounded shows two distinct movements of the polymerase by substrate or analogue binding. The model of the complex with the template:primer derived by superimposition with foot-and-mouth disease virus (FMDV) 3D/RNA complex reveals the likely recognition and binding of template:primer RNA by the polymerase. These results together provide a molecular basis for EV71 RNA replication and reveal a potential target for anti-EV71 drug discovery.

Cite this article

Yang Wu, Zhiyong Lou, Yi Miao, Yue Yu, Hui Dong, Wei Peng, Mark Bartlam, Xuemei Li, Zihe Rao . Structures of EV71 RNA-dependent RNA polymerase in complex with substrate and analogue provide a drug target against the hand-foot-and-mouth disease pandemic in China[J]. Protein & Cell, 2010 , 1(5) : 491 -500 . DOI: 10.1007/s13238-010-0061-7

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