Structure and mechanism of a canonical poly(ADP-ribose) glycohydrolase.
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.
Manchester Interdisciplinary Biocentre, Princess Street 131, M1 7DN, Manchester, UK.
Mark S
MS
Dunstan
Eva
E
Barkauskaite
Pierre
P
Lafite
Claire E
CE
Knezevic
Amy
A
Brassington
Marijan
M
Ahel
Paul J
PJ
Hergenrother
David
D
Leys
Ivan
I
Ahel
D006026:Glycoside Hydrolases / Q000737:chemistry* / Q000145:classification / Q000378:metabolism; D006801:Humans; D010802:Phylogeny; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D016808:Tetrahymena thermophila / Q000201:enzymology
D006026:Glycoside Hydrolases; C022407:poly ADP-ribose glycohydrolase