Binding of 2'-amino-2'-deoxycytidine-5'-triphosphate to norovirus polymerase induces rearrangement of the active site.
Crystal structures of a genogroup II.4 human norovirus polymerase bound to an RNA primer-template duplex and the substrate analogue 2'-amino-2'-deoxycytidine-5'-triphosphate have been determined to 1.8 A resolution. The alteration of the substrate-binding site that is required to accommodate the 2'-amino group leads to a rearrangement of the polymerase active site and a disruption of the coordination shells of the active-site metal ions. The mode of binding seen for 2'-amino-2'-deoxycytidine-5'-triphosphate suggests a novel molecular mechanism of inhibition that may be exploited for the design of inhibitors targeting viral RNA polymerases.
Zamyatkin
Dmitry F
DF
Department of Biological Sciences and Alberta Ingenuity Centre for Carbohydrate Science, University of Calgary, Canada.
Parra
Francisco
F
Machín
Angeles
A
Grochulski
Pawel
P
Ng
Kenneth K-S
KK
D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D003570:Cytidine Triphosphate / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D029322:Norovirus / Q000737:chemistry*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012324:RNA-Dependent RNA Polymerase / Q000737:chemistry* / Q000378:metabolism*; D014764:Viral Proteins / Q000737:chemistry* / Q000378:metabolism*
C541793:2'-amino-2'-deoxycytidine-5'-triphosphate; D004791:Enzyme Inhibitors; D014764:Viral Proteins; D003570:Cytidine Triphosphate; D012324:RNA-Dependent RNA Polymerase