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.
Department of Biological Sciences and Alberta Ingenuity Centre for Carbohydrate Science, University of Calgary, Canada.
Dmitry F
DF
Zamyatkin
Francisco
F
Parra
Angeles
A
Machín
Pawel
P
Grochulski
Kenneth K-S
KK
Ng
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