Putative functional domains of human cytomegalovirus pUL56 involved in dimerization and benzimidazole D-ribonucleoside activity.
BACKGROUND
Benzimidazole D-ribonucleosides inhibit DNA packaging during human cytomegalovirus (HCMV) replication. Although they have been shown to target pUL56 and pUL89 (the large and small subunits of the HCMV terminase, respectively) their mechanism of action is not yet fully understood. We aimed here to better understand HCMV DNA maturation and the mechanism of action of benzimidazole derivatives.


METHODS
The HCMV pUL56 protein was studied by sequence analysis of the HCMV UL56 gene and herpesvirus counterparts combined with primary structure analysis of the corresponding amino acid sequences.


RESULTS
The UL56 sequence analysis of 45 HCMV strains and counterparts among herpesviruses allowed the identification of 12 conserved regions. Moreover, comparison with the product of gene 49 (gp49) of bacteriophage T4 suggested that the pUL56 zinc finger is localized close to the dimerization site of pUL56, providing a spatial organization of the catalytic site that allows recognition and cleavage of DNA.


CONCLUSIONS
This study provides a basis to investigate the mechanism of concatemeric DNA cleavage and a biochemical basis for DNA packaging inhibition by benzimidazole derivatives.
Champier
Gaël
G
Université de Limoges, Faculté de Médecine, Centre Hospitalier Universitaire Dupuytren, EA 3175, Laboratoire de Bactériologie-Virologie-Hygiène, Centre National de Référence Cytomégalovirus, Limoges, France.
Couvreux
Anthony
A
Hantz
Sébastien
S
Rametti
Armelle
A
Mazeron
Marie-Christine
MC
Bouaziz
Serge
S
Denis
François
F
Alain
Sophie
S
D000595:Amino Acid Sequence; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D004279:DNA, Viral / Q000378:metabolism; D019281:Dimerization; D005347:Fibroblasts; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D012263:Ribonucleosides / Q000737:chemistry / Q000494:pharmacology*; D017422:Sequence Analysis, DNA; D015678:Viral Structural Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D019065:Virus Assembly / Q000187:drug effects
D001562:Benzimidazoles; D004279:DNA, Viral; D012263:Ribonucleosides; C090238:UL56 protein, cytomegalovirus; D015678:Viral Structural Proteins; C031000:benzimidazole