Active site cavity of herpesvirus proteases revealed by the crystal structure of herpes simplex virus protease/inhibitor complex.
Human herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) are responsible for herpes labialis (cold sores) and genital herpes, respectively. They encode a serine protease that is required for viral replication, and represent a viable target for therapeutic intervention. Here, we report the crystal structures of HSV-1 and HSV-2 proteases, the latter in the presence and absence of the covalently bound transition state analog inhibitor diisopropyl phosphate (DIP). The HSV-1 and HSV-2 protease structures show a fold that is neither like chymotrypsin nor like subtilisin, and has been seen only in the recently determined cytomegalovirus (CMV) and varicella-zoster virus (VZV) protease structures. HSV-1 and HSV-2 proteases share high sequence homology and have almost identical three-dimensional structures. However, structural differences are observed with the less homologous CMV protease, offering a structural basis for herpes virus protease ligand specificity. The bound inhibitor identifies the oxyanion hole of these enzymes and defines the active site cavity.
Hoog
S S
SS
Department of Macromolecular Sciences, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA.
Smith
W W
WW
Qiu
X
X
Janson
C A
CA
Hellmig
B
B
McQueney
M S
MS
O'Donnell
K
K
O'Shannessy
D
D
DiLella
A G
AG
Debouck
C
C
Abdel-Meguid
S S
SS
D001665:Binding Sites; D002213:Capsid / Q000737:chemistry* / Q000235:genetics; D018360:Crystallography, X-Ray; D018259:Herpesvirus 1, Human / Q000201:enzymology*; D018258:Herpesvirus 2, Human / Q000201:enzymology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009943:Organophosphorus Compounds / Q000737:chemistry*; D011480:Protease Inhibitors; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000737:chemistry; D012697:Serine Endopeptidases / Q000737:chemistry* / Q000235:genetics; D014764:Viral Proteins
D009943:Organophosphorus Compounds; D011480:Protease Inhibitors; D011994:Recombinant Proteins; D014764:Viral Proteins; C079287:scaffold protein, Herpes simplex virus-1; C002226:diisopropylphosphate; C109246:HSV-2 protease; D012697:Serine Endopeptidases