Journal
PROTEIN & CELL
Volume 1, Issue 5, Pages 491-500Publisher
OXFORD UNIV PRESS
DOI: 10.1007/s13238-010-0061-7
Keywords
enterovirus 71; RNA-dependent RNA polymerase; crystal structure; drug target
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Funding
- National Basic Research Program (973 Program)
- National Programs for High Technology Research and Development Program (863 Program) [2006CB806503, 2006AA020502]
- National Major Project [2009ZX10004-304, 2009ZX09311-001]
- Tsinghua University Initiative Scientific Research Program [2009THZ01]
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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 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 angstrom 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.
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