Structure and mechanism of a canonical poly(ADP-ribose) glycohydrolase

Mark S. Dunstan; Eva Barkauskaite; Pierre Lafite; Claire E. Knezevic; Amy Brassington; Marijan Ahel; Paul J. Hergenrother; David Leys; Ivan Ahel

doi:10.1038/ncomms1889

Structure and mechanism of a canonical poly(ADP-ribose) glycohydrolase

Mark S. Dunstan, Eva Barkauskaite, Pierre Lafite, Claire E. Knezevic, Amy Brassington, Marijan Ahel, Paul J. Hergenrother, David Leys^*, Ivan Ahel

^*Corresponding author for this work

Pathology

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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 (1ĝ€2ĝ€ 2-2ĝ€2) riboseĝ€"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.

Original language	English (US)
Article number	878
Journal	Nature communications
Volume	3
DOIs	https://doi.org/10.1038/ncomms1889
State	Published - 2012

Funding

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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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 (1ĝ€2ĝ€ 2-2ĝ€2) riboseĝ€{"}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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AU - Dunstan, Mark S.

AU - Barkauskaite, Eva

AU - Lafite, Pierre

AU - Knezevic, Claire E.

AU - Brassington, Amy

AU - Ahel, Marijan

AU - Hergenrother, Paul J.

AU - Leys, David

AU - Ahel, Ivan

PY - 2012

Y1 - 2012

N2 - 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 (1ĝ€2ĝ€ 2-2ĝ€2) riboseĝ€"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.

AB - 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 (1ĝ€2ĝ€ 2-2ĝ€2) riboseĝ€"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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Structure and mechanism of a canonical poly(ADP-ribose) glycohydrolase

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