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

Research output: Contribution to journalArticlepeer-review

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 languageEnglish (US)
Article number878
JournalNature communications
Volume3
DOIs
StatePublished - 2012

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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