STRUCTURE OF THE RNA-DEPENDENT RNA-POLYMERASE OF POLIOVIRUS

Background: The central player in the replication of RNA Viruses is th e viral RNA-dependent RNA polymerase. The 53 kDa poliovirus polymerase , together with other viral and possibly host proteins, carries out vi ral RNA replication in the host cell cytoplasm. RNA-dependent RNA poly merases comprise a distinct category of polymerases that have limited sequence similarity to reverse transcriptases (RNA-dependent DNA polym erases) and perhaps also to DNA-dependent polymerases, Previously repo rted structures of RNA-dependent DNA polymerases, DNA-dependent DNA po lymerases and a DNA-dependent RNA polymerase show that structural and evolutionary relationships exist between the different polymerase cate gories. Results: We have determined the structure of the RNA-dependent RNA polymerase of poliovirus at 2.6 Angstrom resolution by X-ray crys tallography. It has the same overall shape as other polymerases, commo nly described by analogy to a right hand. The structures of the 'finge rs' and 'thumb' subdomains of poliovirus polymerase differ from those of other polymerases, but the palm subdomain contains a core structure very similar to that of other polymerases. This conserved core struct ure is composed of four of the amino acid sequence motifs described fo r RNA-dependent polymerases. Structure-based alignments of these motif s has enabled us to modify and extend previous sequence and structural alignments so as to relate sequence conservation to function. Extensi ve regions of polymerase-polymerase interactions observed in the cryst als suggest an unusual higher order structure that we believe is impor tant for polymerase function. Conclusions: As a first example of a str ucture of an RNA-dependent RNA polymerase, the poliovirus polymerase s tructure provides for a better understanding of polymerase structure, function and evolution. In addition, it has yielded insights into an u nusual higher order structure that may be critical for poliovirus poly merase function.