Structural basis of selective inhibition of human tankyrases.
Tankyrases are poly(ADP-ribose) polymerases that have many cellular functions. They play pharmaceutically important roles, at least in telomere homeostasis and Wnt signaling, by covalently ADP-ribosylating target proteins and consequently regulating their functions. These features make tankyrases potential targets for treatment of cancer. We report here crystal structures of human tankyrase 2 catalytic fragment in complex with a byproduct, nicotinamide, and with selective inhibitors of tankyrases (IWR-1) and PARPs 1 and 2 (olaparib). Binding of these inhibitors to tankyrase 2 induces specific conformational changes. The crystal structures explain the selectivity of the inhibitors, reveal the flexibility of a substrate binding loop, and explain existing structure-activity relationship data. The first crystal structure of a PARP enzyme in complex with a potent inhibitor, IWR-1, that does not bind to the widely utilized nicotinamide-binding site makes the structure valuable for development of PARP inhibitors in general.
Pharmaceutical Sciences, Department of Biosciences, Abo Akademi University, FI-20520 Turku, Finland.
Mohit
M
Narwal
Harikanth
H
Venkannagari
Lari
L
Lehtiö
D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D057075:Enzyme Assays; D006801:Humans; D008958:Models, Molecular; D009536:Niacinamide / Q000737:chemistry; D010793:Phthalazines / Q000737:chemistry; D010879:Piperazines / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D011804:Quinolines / Q000737:chemistry; D013329:Structure-Activity Relationship; D038501:Tankyrases / Q000037:antagonists & inhibitors* / Q000737:chemistry
D010793:Phthalazines; D010879:Piperazines; D011804:Quinolines; D009536:Niacinamide; C437334:TNKS2 protein, human; D038501:Tankyrases; C531550:olaparib