Structural insights into mechanisms of catalysis and inhibition in Norwalk virus polymerase

Dmitry F. Zamyatkin, Francisco Parra, José M. Martín Alonso, Daniel A. Harki, Blake R. Peterson, Pawel Grochulski, Kenneth K.S. Ng

Research output: Contribution to journalArticlepeer-review

131 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)7705-7712
Number of pages8
JournalJournal of Biological Chemistry
Volume283
Issue number12
DOIs
StatePublished - Mar 21 2008

Fingerprint

Dive into the research topics of 'Structural insights into mechanisms of catalysis and inhibition in Norwalk virus polymerase'. Together they form a unique fingerprint.

Cite this