3MJR

Human dCK complex with Acyclic Nucleoside

3MJR の概要

• エントリーDOI: 10.2210/pdb3mjr/pdb
• 分子名称: Deoxycytidine kinase, 9-HYROXYETHOXYMETHYLGUANINE, URIDINE-5'-DIPHOSPHATE, ... (4 entities in total)
• 機能のキーワード: acv, gcv, dck, kinase, udp, p-loop, kinase activity, nucleoside kinase, transferase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Nucleus : P27707
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 132582.30

構造登録者

Hazra, S.,Lavie, A. (登録日: 2010-04-13, 公開日: 2010-07-28, 最終更新日: 2023-09-06)

主引用文献

Hazra, S.,Konrad, M.,Lavie, A.
The Sugar Ring of the Nucleoside Is Required for Productive Substrate Positioning in the Active Site of Human Deoxycytidine Kinase (dCK): Implications for the Development of dCK-Activated Acyclic Guanine Analogues.
J.Med.Chem., 53:5792-5800, 2010

PubMed Abstract: The low toxicity of acyclovir (ACV) is mainly due to the fact that human nucleoside kinases have undetectable phosphorylation rates with this acyclic guanine analogue. In contrast, herpes virus thymidine kinase (HSV1-TK) readily activates ACV. We wanted to understand why human deoxycytidine kinase (dCK), which is related to HSV1-TK and phosphorylates deoxyguanosine, does not accept acyclic guanine analogues as substrates. Therefore, we crystallized dCK in complex with ACV at the nucleoside phosphoryl acceptor site and UDP at the phosphoryl donor site. The structure reveals that while ACV does bind at the dCK active site, it does so adopting a nonproductive conformation. Despite binding ACV, the enzyme remains in the open, inactive state. In comparison to ACV binding to HSV1-TK, in dCK, the nucleoside base adopts a different orientation related by about a 60 degrees rotation. Our analysis suggests that dCK would phosphorylate acyclic guanine analogues if they can induce a similar rotation.

PubMed: 20684612
DOI: 10.1021/jm1005379

実験手法

X-RAY DIFFRACTION (2.1 Å)