Zinc binding catalytic domain of human tankyrase 1.
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.
Lehtiö
Lari
L
Structural Genomics Consortium, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-17177 Stockholm, Sweden.
Collins
Ruairi
R
van den Berg
Susanne
S
Johansson
Andreas
A
Dahlgren
Lars-Göran
LG
Hammarström
Martin
M
Helleday
Thomas
T
Holmberg-Schiavone
Lovisa
L
Karlberg
Tobias
T
Weigelt
Johan
J
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*
D004791:Enzyme Inhibitors; D038501:Tankyrases; D015032:Zinc; C437334:TNKS2 protein, human; C418109:TNKS protein, human