title: Zinc binding catalytic domain of human tankyrase 1.
abstract: Tankyrases are recently discovered proteins implicated in many important functions in the cell including telomere homeostasis and mitosis. Tankyrase modulates the activity of target proteins through poly(ADP-ribosyl)ation, and here we report the structure of the catalytic poly(ADP-ribose) polymerase (PARP) domain of human tankyrase 1. This is the first structure of a PARP domain from the tankyrase subfamily. The present structure reveals that tankyrases contain a short zinc-binding motif, which has not been predicted. Tankyrase activity contributes to telomere elongation observed in various cancer cells and tankyrase inhibition has been suggested as a potential route for cancer therapy. In comparison with other PARPs, significant structural differences are observed in the regions lining the substrate-binding site of tankyrase 1. These findings will be of great value to facilitate structure-based design of selective PARP inhibitors, in general, and tankyrase inhibitors, in particular.
authors.affiliation: Structural Genomics Consortium, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-17177 Stockholm, Sweden.
authors.forename: Lari
authors.initials: L
authors.lastname: Lehtiö
authors.forename: Ruairi
authors.initials: R
authors.lastname: Collins
authors.forename: Susanne
authors.initials: S
authors.lastname: van den Berg
authors.forename: Andreas
authors.initials: A
authors.lastname: Johansson
authors.forename: Lars-Göran
authors.initials: LG
authors.lastname: Dahlgren
authors.forename: Martin
authors.initials: M
authors.lastname: Hammarström
authors.forename: Thomas
authors.initials: T
authors.lastname: Helleday
authors.forename: Lovisa
authors.initials: L
authors.lastname: Holmberg-Schiavone
authors.forename: Tobias
authors.initials: T
authors.lastname: Karlberg
authors.forename: Johan
authors.initials: J
authors.lastname: Weigelt
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D001665:Binding Sites; D020134:Catalytic Domain; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry; D006801:Humans; D008969:Molecular Sequence Data; D015394:Molecular Structure; D038501:Tankyrases / Q000737:chemistry*; D015032:Zinc / Q000737:chemistry*
chemical_list: D004791:Enzyme Inhibitors; D038501:Tankyrases; D015032:Zinc; C437334:TNKS2 protein, human; C418109:TNKS protein, human