Structural Dynamics of Picornaviral RdRP Complexes. Implications for the Design of Antivirals
Genome replication in picornavirus is catalyzed by a virally encoded RNA dependent RNA polymerase, termed 3D. These viruses also use a small protein primer, named VPg to initiate RNA replication. Polymerase 3D also catalyzes the covalent linkage of UMP to a N-terminal tyrosine on VPg. Seven different crystal structures of foot-and-mouth disease virus (FMDV) 3D catalytic complexes have enhanced our understanding of template and primer recognition, VPg uridylylation and rNTP binding and catalysis. In addition, the biochemical and structural analyses of six different FMDV 3D ribavirin resistant mutants provided evidences of three different mechanisms of resistance to this mutagenic nucleoside analogue. Such structural information is providing new insights into the fidelity of RNA replication, and for the design of antiviral compounds.
KeywordsPicornavirus RNA-dependent RNA polymerase Replication fidelity Ribavirin
- 1.Agudo R, Ferrer-Orta C, Arias A, de la Higuera I, Perales C, Pérez-Luque R, Verdaguer N, Domingo E (2010) A multi-step process of viral adaptation to a mutagenic nucleoside analogue by modulation of transition types leads to extinction-escape. PLoS Pathog. 2010 Aug 26; 6(8) pii: e1001072Google Scholar
- 2.Arias A, Arnold JJ, Sierra M, Smidansky ED, Domingo E, Cameron CE (2008) Determinants of RNA-dependent RNA polymerase (in)fidelity revealed by kinetic analysis of the polymerase encoded by a foot-and-mouth disease virus mutant with reduced sensitivity to ribavirin. J Virol 82:12346–12355CrossRefGoogle Scholar
- 8.Domingo E, Parrish C, Holland JJE (2008) Origin and evolution of viruses, 2nd edn. Elsevier, OxfordGoogle Scholar