TY - JOUR
T1 - Structural insights into mechanisms of catalysis and inhibition in Norwalk virus polymerase
AU - Zamyatkin, Dmitry F.
AU - Parra, Francisco
AU - Martín Alonso, José M.
AU - Harki, Daniel A.
AU - Peterson, Blake R.
AU - Grochulski, Pawel
AU - Ng, Kenneth K.S.
PY - 2008/3/21
Y1 - 2008/3/21
N2 - Crystal structures of Norwalk virus polymerase bound to an RNA primer-template duplex and either the natural substrate CTP or the inhibitor 5-nitrocytidine triphosphate have been determined to 1.8 A° resolution. These structures reveal a closed conformation of the polymerase that differs significantly from previously determined open structures of calicivirus and picornavirus polymerases. These closed complexes are trapped immediately prior to the nucleotidyl transfer reaction, with the triphosphate group of the nucleotide bound to two manganese ions at the active site, poised for reaction to the 3′-hydroxyl group of the RNA primer. The positioning of the 5-nitrocytidine triphosphate nitro group between the α-phosphate and the 3′-hydroxyl group of the primer suggests a novel, general approach for the design of antiviral compounds mimicking natural nucleosides and nucleotides.
AB - Crystal structures of Norwalk virus polymerase bound to an RNA primer-template duplex and either the natural substrate CTP or the inhibitor 5-nitrocytidine triphosphate have been determined to 1.8 A° resolution. These structures reveal a closed conformation of the polymerase that differs significantly from previously determined open structures of calicivirus and picornavirus polymerases. These closed complexes are trapped immediately prior to the nucleotidyl transfer reaction, with the triphosphate group of the nucleotide bound to two manganese ions at the active site, poised for reaction to the 3′-hydroxyl group of the RNA primer. The positioning of the 5-nitrocytidine triphosphate nitro group between the α-phosphate and the 3′-hydroxyl group of the primer suggests a novel, general approach for the design of antiviral compounds mimicking natural nucleosides and nucleotides.
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U2 - 10.1074/jbc.M709563200
DO - 10.1074/jbc.M709563200
M3 - Article
C2 - 18184655
AN - SCOPUS:43149087336
SN - 0021-9258
VL - 283
SP - 7705
EP - 7712
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 12
ER -