4L2H

Structure of a catalytically inactive PARG in complex with a poly-ADP-ribose fragment

Summary for 4L2H

• Entry DOI: 10.2210/pdb4l2h/pdb
• Descriptor: Poly(ADP-ribose) glycohydrolase, [(2R,3S,4R,5R)-5-(6-AMINOPURIN-9-YL)-3,4-DIHYDROXY-OXOLAN-2-YL]METHYL [HYDROXY-[[(2R,3S,4R,5S)-3,4,5-TRIHYDROXYOXOLAN-2-YL]METHOXY]PHOSPHORYL] HYDROGEN PHOSPHATE (3 entities in total)
• Functional Keywords: macrodomain, poly-adp-ribose glycohydrolase, poly-adp-ribose, hydrolase
• Biological source: Tetrahymena thermophila
• Total number of polymer chains: 1
• Total formula weight: 57003.67

Authors

Brassington, A.,Dunstan, M.S.,Leys, D. (deposition date: 2013-06-04, release date: 2013-07-24, Last modification date: 2023-09-20)

Primary citation

Barkauskaite, E.,Brassington, A.,Tan, E.S.,Warwicker, J.,Dunstan, M.S.,Banos, B.,Lafite, P.,Ahel, M.,Mitchison, T.J.,Ahel, I.,Leys, D.
Visualization of poly(ADP-ribose) bound to PARG reveals inherent balance between exo- and endo-glycohydrolase activities.
Nat Commun, 4:2164-2164, 2013

PubMed Abstract: Poly-ADP-ribosylation is a post-translational modification that regulates processes involved in genome stability. Breakdown of the poly(ADP-ribose) (PAR) polymer is catalysed by poly(ADP-ribose) glycohydrolase (PARG), whose endo-glycohydrolase activity generates PAR fragments. Here we present the crystal structure of PARG incorporating the PAR substrate. The two terminal ADP-ribose units of the polymeric substrate are bound in exo-mode. Biochemical and modelling studies reveal that PARG acts predominantly as an exo-glycohydrolase. This preference is linked to Phe902 (human numbering), which is responsible for low-affinity binding of the substrate in endo-mode. Our data reveal the mechanism of poly-ADP-ribosylation reversal, with ADP-ribose as the dominant product, and suggest that the release of apoptotic PAR fragments occurs at unusual PAR/PARG ratios.

PubMed: 23917065
DOI: 10.1038/ncomms3164

Experimental method

X-RAY DIFFRACTION (1.46 Å)