title: Structural basis for the specificity, catalysis, and regulation of human uridine-cytidine kinase.
abstract: 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 alpha/beta 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.
authors.affiliation: Department of Structural Biology, Graduate School of Pharmaceutical Sciences, Hokkaido University, N12 W6 Kita-ku, Sapporo 060-0812, Japan.
authors.forename: Nobuo N
authors.initials: NN
authors.lastname: Suzuki
authors.forename: Katsuhisa
authors.initials: K
authors.lastname: Koizumi
authors.forename: Masanori
authors.initials: M
authors.lastname: Fukushima
authors.forename: Akira
authors.initials: A
authors.lastname: Matsuda
authors.forename: Fuyuhiko
authors.initials: F
authors.lastname: Inagaki
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000595:Amino Acid Sequence; D001665:Binding Sites; D025461:Feedback, Physiological / Q000502:physiology; D006801:Humans; D008024:Ligands; D008969:Molecular Sequence Data; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D013379:Substrate Specificity; D014461:Ultracentrifugation; D014541:Uridine Kinase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism
chemical_list: D008024:Ligands; D000255:Adenosine Triphosphate; D014541:Uridine Kinase