Rack, J.G.M., Ariza, A. orcid.org/0000-0003-4364-823X, Drown, B.S. et al. (5 more authors) (2018) (ADP-ribosyl)hydrolases: structural basis for differential substrate recognition and inhibition. Cell Chemical Biology, 25 (12). E12. pp. 1533-1546. ISSN 2451-9456
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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2018 The Authors. This is an Open Access article distributed under the terms of the Creative Commons Attribution Licence (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
Keywords: | ADP-ribosylation; ADPRH; ADPRHL2; DNA damage; PARG; PARP; metalloenzyme; Adaptor Proteins, Signal Transducing; Dose-Response Relationship, Drug; Enzyme Inhibitors; Glycoside Hydrolases; Humans; Models, Molecular; Protein Conformation; Structure-Activity Relationship; Substrate Specificity |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Science (Sheffield) > School of Biosciences (Sheffield) |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 09 Jun 2023 14:25 |
Last Modified: | 09 Jun 2023 14:25 |
Status: | Published |
Publisher: | Elsevier BV |
Refereed: | Yes |
Identification Number: | 10.1016/j.chembiol.2018.11.001 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:199681 |