2W0S

Crystal structure of vaccinia virus thymidylate kinase bound to brivudin-5'-monophosphate

2W0S の概要

• エントリーDOI: 10.2210/pdb2w0s/pdb
• 関連するPDBエントリー: 2V54
• 分子名称: THYMIDYLATE KINASE, MAGNESIUM ION, (E)-5-(2-BROMOVINYL)-2'-DEOXYURIDINE-5'-MONOPHOSPHATE, ... (5 entities in total)
• 機能のキーワード: nucleotide biosynthesis, atp-binding, nucleotide-binding, kinase, poxvirus, tmp kinase, transferase
• 由来する生物種: VACCINIA VIRUS COPENHAGEN
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 48015.85

構造登録者

Caillat, C.,Topalis, D.,Agrofoglio, L.A.,Pochet, S.,Balzarini, J.,Deville-Bonne, D.,Meyer, P. (登録日: 2008-10-08, 公開日: 2008-10-21, 最終更新日: 2023-12-13)

主引用文献

Caillat, C.,Topalis, D.,Agrofoglio, L.A.,Pochet, S.,Balzarini, J.,Deville-Bonne, D.,Meyer, P.
Crystal Structure of Poxvirus Thymidylate Kinase: An Unexpected Dimerization Has Implications for Antiviral Therapy
Proc.Natl.Acad.Sci.USA, 105:16900-, 2008

PubMed Abstract: Unlike most DNA viruses, poxviruses replicate in the cytoplasm of host cells. They encode enzymes needed for genome replication and transcription, including their own thymidine and thymidylate kinases. Some herpes viruses encode only 1 enzyme catalyzing both reactions, a peculiarity used for prodrug activation to obtain maximum specificity. We have solved the crystal structures of vaccinia virus thymidylate kinase bound to TDP or brivudin monophosphate. Although the viral and human enzymes have similar sequences (42% identity), they differ in their homodimeric association and active-site geometry. The vaccinia TMP kinase dimer arrangement is orthogonal and not antiparallel as in human enzyme. This different monomer orientation is related to the presence of a canal connecting the edge of the dimer interface to the TMP base binding pocket. Consequently, the pox enzyme accommodates nucleotides with bulkier bases, like brivudin monophosphate and dGMP; these are efficiently phosphorylated and stabilize the enzyme. The brivudin monophosphate-bound structure explains the structural basis for this specificity, opening the way to the rational development of specific antipox agents that may also be suitable for poxvirus TMP kinase gene-based chemotherapy of cancer.

PubMed: 18971333
DOI: 10.1073/PNAS.0804525105

実験手法

X-RAY DIFFRACTION (2.918 Å)