1OSN

Crystal structure of Varicella zoster virus thymidine kinase in complex with BVDU-MP and ADP

1OSN の概要

• エントリーDOI: 10.2210/pdb1osn/pdb
• 分子名称: Thymidine kinase, ADENOSINE-5'-DIPHOSPHATE, (E)-5-(2-BROMOVINYL)-2'-DEOXYURIDINE-5'-MONOPHOSPHATE, ... (4 entities in total)
• 機能のキーワード: human herpes virus 3, chickenpox, thymidine kinase, bvdu-mp, transferase
• 由来する生物種: Human herpesvirus 3 (Varicella-zoster virus)
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 154884.64

構造登録者

Bird, L.E.,Ren, J.,Wright, A.,Leslie, K.D.,Degreve, B.,Balzarini, J.,Stammers, D.K. (登録日: 2003-03-20, 公開日: 2003-06-10, 最終更新日: 2023-10-25)

主引用文献

Bird, L.E.,Ren, J.,Wright, A.,Leslie, K.D.,Degreve, B.,Balzarini, J.,Stammers, D.K.
Crystal structure of varicella zoster virus thymidine kinase
J.Biol.Chem., 278:24680-24687, 2003

PubMed Abstract: Herpes virus thymidine kinases are responsible for the activation of nucleoside antiviral drugs including (E)-5-(2-bromovinyl)-2'-deoxyuridine. Such viral thymidine kinases (tk), beside having a broader substrate specificity compared with host cell enzymes, also show significant variation in nucleoside phosphorylation among themselves. We have determined the crystal structure of Varicella zoster virus (VZV, human herpes virus 3) thymidine kinase complexed with (E)-5-(2-bromovinyl)-2'-deoxyuridine 5'-monophosphate and ADP. Differences in the conformation of a loop region (residues 55-61) and the position of two alpha-helices at the subunit interface of VZV-tk compared with the herpes simplex virus type 1 (human herpes virus 1) enzyme give rise to changes in the positioning of residues such as tyrosine 66 and glutamine 90, which hydrogen bond to the substrate in the active site. Such changes in combination with the substitution in VZV-tk of two phenylalanine residues (in place of a tyrosine and methionine), which sandwich the substrate pyrimidine ring, cause an alteration in the positioning of the base. The interaction of the (E)-5-(2-bromovinyl)-2'-deoxyuridine deoxyribose ring with the protein is altered by substitution of tyrosine 21 and phenylalanine 139 (analagous to herpes simplex virus type 1 histidine 58 and tyrosine 172), which may explain some of the differences in nucleoside sugar selectivity between both enzymes. The altered active site architecture may also account for the differences in the substrate activity of ganciclovir for the two thymidine kinases. These data should be of use in the design of novel antiherpes and antitumor drugs.

PubMed: 12686543
DOI: 10.1074/jbc.M302025200

実験手法

X-RAY DIFFRACTION (3.2 Å)