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Instruments / Technical Area	Publication Details	Published	Actions
I04-Macromolecular Crystallography	The structure and catalytic mechanism of a poly(ADP-ribose) glycohydrolase Dea Slade , Mark S. Dunstan , Eva Barkauskaite , Ria Weston , Pierre Lafite , Neil Dixon , Marijan Ahel , David Leys , Ivan Ahel Nature 477, 616 - 620 DOI: 10.1038/nature10404 PMID: 21892188 Open Access Show Abstract ▼ Abstract: Post-translational modification of proteins by poly(ADP-ribosyl)ation regulates many cellular pathways that are critical for genome stability, including DNA repair, chromatin structure, mitosis and apoptosis1. Poly(ADP-ribose) (PAR) is composed of repeating ADP-ribose units linked via a unique glycosidic ribose–ribose bond, and is synthesized from NAD by PAR polymerases1, 2. PAR glycohydrolase (PARG) is the only protein capable of specific hydrolysis of the ribose–ribose bonds present in PAR chains; its deficiency leads to cell death3, 4. Here we show that filamentous fungi and a number of bacteria possess a divergent form of PARG that has all the main characteristics of the human PARG enzyme. We present the first PARG crystal structure (derived from the bacterium Thermomonospora curvata), which reveals that the PARG catalytic domain is a distant member of the ubiquitous ADP-ribose-binding macrodomain family5, 6. High-resolution structures of T. curvata PARG in complexes with ADP-ribose and the PARG inhibitor ADP-HPD, complemented by biochemical studies, allow us to propose a model for PAR binding and catalysis by PARG. The insights into the PARG structure and catalytic mechanism should greatly improve our understanding of how PARG activity controls reversible protein poly(ADP-ribosyl)ation and potentially of how the defects in this regulation are linked to human disease.	Sep 2011

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I04-Macromolecular Crystallography

The structure and catalytic mechanism of a poly(ADP-ribose) glycohydrolase

Dea Slade , Mark S. Dunstan , Eva Barkauskaite , Ria Weston , Pierre Lafite , Neil Dixon , Marijan Ahel , David Leys , Ivan Ahel

Nature 477, 616 - 620

DOI: 10.1038/nature10404

PMID: 21892188