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

DOI: 10.1038/ncomms1889
PMID: 22673905

Authors: Mark Dunstan (University of Manchester) , Eva Barkauskaite (University of Oxford) , Pierre Lafite (Université d'Orléans) , Claire E. Knezevic (University of Illinois at Urbana-Champaign) , Amy Brassington (Manchester Interdisciplinary Biocentre) , Marijan Ahel (Rudjer Boskovic Institute, Zagreb, Croatia) , Paul J. Hergenrother (University of Illinois at Urbana-Champaign) , David Leys (School of Chemistry & Manchester Interdisciplinary Biocentre, The University of Manchester) , Ivan Ahel (Paterson Institute for Cancer Research, University of Manchester,)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Communications , VOL 3 (878) , PAGES 3 (878)

State: Published (Approved)
Published: June 2012
Diamond Proposal Number(s): 7146

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.

Journal Keywords: Humans; Phylogeny; Protein; Secondary; Protein; Tertiary; Tetrahymena thermophila

Subject Areas: Biology and Bio-materials, Medicine, Chemistry


Instruments: I04-Macromolecular Crystallography