Structural basis for the dual thymidine and thymidylate kinase activity of herpes thymidine kinases.
Crystal structures of equine herpesvirus type-4 thymidine kinase (EHV4-TK) in complex with (i). thymidine and ADP, (ii). thymidine and SO(4) and the bisubstrate analogs, (iii). TP(4)A, and (iv). TP(5)A have been solved. Additionally, the structure of herpes simplex virus type-1 thymidine kinase (HSV1-TK) in complex with TP(5)A has been determined. These are the first structures of nucleoside kinases revealing conformational transitions upon binding of bisubstrate analogs. The structural basis for the dual thymidine and thymidylate kinase activity of these TKs is elucidated. While the active sites of HSV1-TK and EHV4-TK resemble one another, notable differences are observed in the Lid regions and in the way the enzymes bind the base of the phosphoryl-acceptor. The latter difference could partly explain the higher activity of EHV4-TK toward the prodrug ganciclovir.
Gardberg
Anna
A
University of Illinois at Chicago, Department of Biochemistry and Molecular Biology, 1819 West Polk St, Chicago, IL 60612, USA.
Shuvalova
Ludmilla
L
Monnerjahn
Christian
C
Konrad
Manfred
M
Lavie
Arnon
A
D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000595:Amino Acid Sequence; D001665:Binding Sites; D018259:Herpesvirus 1, Human / Q000201:enzymology* / Q000378:metabolism; D023141:Herpesvirus 4, Equid / Q000201:enzymology* / Q000378:metabolism; D008969:Molecular Sequence Data; D009703:Nucleoside-Phosphate Kinase / Q000737:chemistry* / Q000378:metabolism; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D013937:Thymidine Kinase / Q000737:chemistry* / Q000378:metabolism
D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D013937:Thymidine Kinase; D009703:Nucleoside-Phosphate Kinase; C020093:dTMP kinase