(ADP-ribosyl)hydrolases: structural basis for differential substrate recognition and inhibition

DOI: 10.1016/j.chembiol.2018.11.001

Authors: Johannes Gregor Matthias Rack (Oxford University) , Antonio Ariza (Oxford University) , Bryon S. Drown (University of Illinois) , Callum Henfrey (Oxford University) , Edward Bartlett (Oxford University; Kyoto Institute of Technology) , Tomohiro Shirai (University of Illinois) , Paul J. Hergenrother (University of Illinois) , Ivan Ahel (Oxford University)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Cell Chemical Biology

State: Published (Approved)
Published: November 2018
Diamond Proposal Number(s): 18069

Abstract: Protein ADP-ribosylation is a highly dynamic post-translational modification. The rapid turnover is achieved, among others, by ADP-(ribosyl)hydrolases (ARHs), an ancient family of enzymes that reverses this modification. Recently ARHs came into focus due to their role as regulators of cellular stresses and tumor suppressors. Here we present a comprehensive structural analysis of the enzymatically active family members ARH1 and ARH3. These two enzymes have very distinct substrate requirements. Our data show that binding of the adenosine ribose moiety is highly diverged between the two enzymes, whereas the active sites harboring the distal ribose closely resemble each other. Despite this apparent similarity, we elucidate the structural basis for the selective inhibition of ARH3 by the ADP-ribose analogues ADP-HPD and arginine-ADP-ribose. Together, our biochemical and structural work provides important insights into the mode of enzyme-ligand interaction, helps to understand differences in their catalytic behavior, and provides useful tools for targeted drug design.

Journal Keywords: ADPRH, ADPRHL2, DNA-damage, ADP-ribosylation, PARP, PARG, metalloenzyme

Diamond Keywords: Enzymes

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

Diamond Offline Facilities: No
Instruments: I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

Other Facilities: No

Added On: 26/11/2018 15:38

Documents:
1-s2.0-S2451945618303891-main.pdf

Discipline Tags:

Health & Wellbeing Biochemistry Catalysis Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)