Structure of the synthetase domain of human CTP synthetase, a target for anticancer therapy.
Cytidine triphosphate synthetase (CTPS) is a key enzyme in nucleic acid and phospholipid biosynthesis and its activity is increased in certain human cancers, making it a promising drug target. The crystal structure of the synthetase domain of human CTPS, which represents the first structure of a CTPS from an eukaryote, has been determined. The structure is homotetrameric and each active site is formed by three different subunits. Sulfate ions bound to the active sites indicate the positions of phosphate-binding sites for the substrates ATP and UTP and the feedback inhibitor CTP. Together with earlier structures of bacterial CTPS, the human CTPS structure provides an extended understanding of the structure-function relationship of CTPS-family members. The structure also serves as a basis for structure-based design of anti-proliferative inhibitors.
Kursula
Petri
P
Structural Genomics Consortium, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-17177 Stockholm, Sweden.
Flodin
Susanne
S
Ehn
Maria
M
Hammarström
Martin
M
Schüler
Herwig
H
Nordlund
Pär
P
Stenmark
Pål
P
D000595:Amino Acid Sequence; D000970:Antineoplastic Agents; D001665:Binding Sites; D019731:Carbon-Nitrogen Ligases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000302:isolation & purification; D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D004926:Escherichia coli / Q000201:enzymology; D005246:Feedback; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011994:Recombinant Proteins / Q000737:chemistry
D000970:Antineoplastic Agents; D011994:Recombinant Proteins; D019731:Carbon-Nitrogen Ligases; C019951:CTP synthetase