Crystal structure of the herpes simplex virus 1 DNA polymerase.
Herpesviruses are the second leading cause of human viral diseases. Herpes Simplex Virus types 1 and 2 and Varicella-zoster virus produce neurotropic infections such as cutaneous and genital herpes, chickenpox, and shingles. Infections of a lymphotropic nature are caused by cytomegalovirus, HSV-6, HSV-7, and Epstein-Barr virus producing lymphoma, carcinoma, and congenital abnormalities. Yet another series of serious health problems are posed by infections in immunocompromised individuals. Common therapies for herpes viral infections employ nucleoside analogs, such as Acyclovir, and target the viral DNA polymerase, essential for viral DNA replication. Although clinically useful, this class of drugs exhibits a narrow antiviral spectrum, and resistance to these agents is an emerging problem for disease management. A better understanding of herpes virus replication will help the development of new safe and effective broad spectrum anti-herpetic drugs that fill an unmet need. Here, we present the first crystal structure of a herpesvirus polymerase, the Herpes Simplex Virus type 1 DNA polymerase, at 2.7 A resolution. The structural similarity of this polymerase to other alpha polymerases has allowed us to construct high confidence models of a replication complex of the polymerase and of Acyclovir as a DNA chain terminator. We propose a novel inhibition mechanism in which a representative of a series of non-nucleosidic viral polymerase inhibitors, the 4-oxo-dihydroquinolines, binds at the polymerase active site interacting non-covalently with both the polymerase and the DNA duplex.
Liu
Shenping
S
Exploratory Medicinal Sciences, Pfizer Inc., Eastern Point Road, Groton, CT 06340, USA. shenping.liu@pfizer.com
Knafels
John D
JD
Chang
Jeanne S
JS
Waszak
Gregory A
GA
Baldwin
Eric T
ET
Deibel
Martin R
MR
Thomsen
Darrell R
DR
Homa
Fred L
FL
Wells
Peter A
PA
Tory
Monica C
MC
Poorman
Roger A
RA
Gao
Hua
H
Qiu
Xiayang
X
Seddon
Andrew P
AP
D000212:Acyclovir / Q000737:chemistry; D000998:Antiviral Agents / Q000737:chemistry; D001665:Binding Sites; D003461:Crystallography; D004259:DNA-Directed DNA Polymerase / Q000737:chemistry*; D015195:Drug Design; D024882:Drug Resistance, Viral; D005090:Exodeoxyribonucleases / Q000737:chemistry*; D018259:Herpesvirus 1, Human / Q000187:drug effects / Q000201:enzymology*; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011804:Quinolines / Q000737:chemistry; D014764:Viral Proteins / Q000737:chemistry*
D000998:Antiviral Agents; D011804:Quinolines; D014764:Viral Proteins; D004259:DNA-Directed DNA Polymerase; D005090:Exodeoxyribonucleases; C043417:DNA polymerase, Simplexvirus; D000212:Acyclovir