Three-dimensional modeling of cytomegalovirus DNA polymerase and preliminary analysis of drug resistance.

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Shi R, Azzi A, Gilbert C, Boivin G, Lin SX

Three-dimensional modeling of cytomegalovirus DNA polymerase and preliminary analysis of drug resistance.

Proteins. 2006 Aug 1;64(2):301-7.

PubMed ID

16705640 [ View in PubMed

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Abstract

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.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Ganciclovir	DNA polymerase catalytic subunit	Protein	HHV-1	Yes	Inhibitor	Details