Structural Basis for the Specificity, Catalysis, and Regulation of Human Uridine-Cytidine Kinase

详细信息    查看全文

• 作者：Suzuki ; Nobuo N. ; Koizumi ; Katsuhisa ; Fukushima ; Masanori ; Matsuda ; Akira ; Inagaki ; Fuyuhiko
• 刊名：Structure
• 出版年：2004
• 出版时间：May, 2004
• 年：2004
• 卷：12
• 期：5
• 页码：751-764
• 全文大小：920 K

文摘

Uridine-cytidine kinase (UCK) catalyzes the phosphorylation of uridine and cytidine and activates pharmacological ribonucleoside analogs. Here we present the crystal structures of human UCK alone and in complexes with a substrate, cytidine, a feedback inhibitor, CTP or UTP, and with phosphorylation products, CMP and ADP, respectively. Free UCK takes an α/β mononucleotide binding fold and exists as a homotetramer with 222 symmetry. Upon inhibitor binding, one loop region was loosened, causing the UCK tetramer to be distorted. Upon cytidine binding, a large induced fit was observed at the uridine/cytidine binding site, which endows UCK with a strict specificity for pyrimidine ribonucleosides. The first UCK structure provided the structural basis for the specificity, catalysis, and regulation of human uridine-cytidine kinase, which give clues for the design of novel antitumor and antiviral ribonucleoside analogs that inhibit RNA synthesis.