title: 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.
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 RNAdependent RNA polymerase (RdRp), denoted 3D(pol), 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 (3D(pol)) and in complex with substrate guanosine-5'-triphosphate and analog 5-bromouridine-5'-triphosphate best to 2.4 Å resolution. The structure of EV71 RdRp (3D(pol)) has a wider open thumb domain compared with the most closely related crystal structure of poliovirus RdRp. And the EV71 RdRp (3D(pol)) 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.
authors.affiliation: National Laboratory of Macromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Wu
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Lou
authors.forename: Yi
authors.initials: Y
authors.lastname: Miao
authors.forename: Yue
authors.initials: Y
authors.lastname: Yu
authors.forename: Hui
authors.initials: H
authors.lastname: Dong
authors.forename: Wei
authors.initials: W
authors.lastname: Peng
authors.forename: Mark
authors.initials: M
authors.lastname: Bartlam
authors.forename: Xuemei
authors.initials: X
authors.lastname: Li
authors.forename: Zihe
authors.initials: Z
authors.lastname: Rao
mesh_terms: D000595:Amino Acid Sequence; D002648:Child; D002681:China / Q000453:epidemiology; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D029821:Enterovirus A, Human / Q000737:chemistry / Q000201:enzymology*; D006232:Hand, Foot and Mouth Disease / Q000188:drug therapy* / Q000453:epidemiology / Q000821:virology*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D058990:Molecular Targeted Therapy; D011487:Protein Conformation; D017510:Protein Folding; D012324:RNA-Dependent RNA Polymerase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment; D013379:Substrate Specificity
chemical_list: D012324:RNA-Dependent RNA Polymerase