Three-dimensional modeling of cytomegalovirus DNA polymerase and preliminary analysis of drug resistance.
Cytomegalovirus (CMV) is the leading cause of congenital infection and a frequent opportunistic agent in immunocompromised hosts such as transplant recipients and AIDS patients. CMV DNA polymerase, a member of the polymerase B family, is the primary target of all available antivirals (ganciclovir, cidofovir, and foscarnet) and certain variations of this enzyme could lead to drug resistance. However, understanding the drug resistance mechanisms at the atomic level is hampered by the lack of its three-dimensional (3D) structure. In the present work, 3D models of two different conformations (closed and open) for CMV DNA polymerase have been built based on the crystal structures of bacteriophage RB69 DNA polymerase (a member of the polymerase B family) by using the 3D-Jury Meta server and the program MODELLER. Most of the variations on CMV DNA polymerase pertinent to ganciclovir/cidofovir and foscarnet resistance can be explained well based on the open and closed conformation models, respectively. These results constitute a first step towards facilitating our understanding of drug resistance mechanisms for CMV and the interpretation of novel viral mutations.
Shi
Rong
R
Research Center in Molecular Endocrinology, Centre Hospitalier Universitaire de Québec (CHUL hospital) and Laval University, Québec City, Canada.
Azzi
Arezki
A
Gilbert
Christian
C
Boivin
Guy
G
Lin
Sheng-Xiang
SX
D000998:Antiviral Agents / Q000494:pharmacology; D001435:Bacteriophages / Q000201:enzymology; D003587:Cytomegalovirus / Q000201:enzymology*; D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D030562:Databases, Protein; D024882:Drug Resistance, Viral; D008958:Models, Molecular; D008968:Molecular Conformation; D009154:Mutation; D011487:Protein Conformation
D000998:Antiviral Agents; D004259:DNA-Directed DNA Polymerase