Structure and mechanism of a canonical poly(ADP-ribose) glycohydrolase.
Dunstan, M Barkauskaite, Eva Lafite, P Knezevic, C Brassington, A Ahel, Marijan Hergenrother, P Leys, D Ahel, I
Dunstan, M
Barkauskaite, Eva
Lafite, P
Knezevic, C
Brassington, A
Ahel, Marijan
Hergenrother, P
Leys, D
Ahel, I
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Abstract
Poly(ADP-ribosyl)ation is a reversible post-translational protein modification involved in the regulation of a number of cellular processes including DNA repair, chromatin structure, mitosis, transcription, checkpoint activation, apoptosis and asexual development. The reversion of poly(ADP-ribosyl)ation is catalysed by poly(ADP-ribose) (PAR) glycohydrolase (PARG), which specifically targets the unique PAR (1''-2') ribose-ribose bonds. Here we report the structure and mechanism of the first canonical PARG from the protozoan Tetrahymena thermophila. In addition, we reveal the structure of T. thermophila PARG in a complex with a novel rhodanine-containing mammalian PARG inhibitor RBPI-3. Our data demonstrate that the protozoan PARG represents a good model for human PARG and is therefore likely to prove useful in guiding structure-based discovery of new classes of PARG inhibitors.
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Date
2012
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Article
Citation
Structure and mechanism of a canonical poly(ADP-ribose) glycohydrolase. 2012, 3:878 Nat Commun