RNA-directed RNA polymerase (RdRp) (EC 18.104.22.168) is an essential protein
encoded in the genomes of all RNA containing viruses with no DNA stage [1,2].
It catalyses synthesis of the RNA strand complementary to a given RNA
template, but the precise molecular mechanism remains unclear. The postulated
RNA replication process is a two-step mechanism. First, the initiation step of
RNA synthesis begins at or near the 3' end of the RNA template by means of a
primer-independent (de novo) mechanism. The de novo initiation consists in the
addition of a nucleotide tri-phosphate (NTP) to the 3'-OH of the first
initiating NTP. During the following so-called elongation phase, this
nucleotidyl transfer reaction is repeated with subsequent NTPs to generate the
complementary RNA product .
All the RNA-directed RNA polymerases, and many DNA-directed polymerases,
employ a fold whose organization has been likened to the shape of a right hand
with three subdomains termed fingers, palm and thumb (see <PDB:1RDR>) .
Only the palm subdomain, composed of a four-stranded antiparallel β-sheet
with two α-helices, is well conserved among all of these enzymes. In RdRp,
the palm subdomain comprises three well conserved motifs (A, B and C). Motif A
(D-x(4,5)-D) and motif C (GDD) are spatially juxtaposed; the Asp residues of
these motifs are implied in the binding of Mg2+ and/or Mn2+. The Asn residue
of motif B is involved in selection of ribonucleoside triphosphates over
dNTPs and thus determines whether RNA is synthesized rather than DNA .
RNA viruses with no DNA stage can be placed in three main categories based on
their replication and coding strategies: positive single-stranded RNA (ssRNA),
negative ssRNA and double-stranded RNA (dsRNA) viruses. To recognize
RNA-directed RNA polymerase we have developed six profiles that roughly follow
this classification (see below). They are all directed against the catalytic
region (palm subdomain).
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