@article{86a21bc7f1eb4cdcb50c160287f9982c,
title = "(ADP-ribosyl)hydrolases: Structural Basis for Differential Substrate Recognition and Inhibition",
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.",
keywords = "ADP-ribosylation, ADPRH, ADPRHL2, DNA damage, PARG, PARP, metalloenzyme",
author = "Rack, {Johannes Gregor Matthias} and Antonio Ariza and Drown, {Bryon S.} and Callum Henfrey and Edward Bartlett and Tomohiro Shirai and Hergenrother, {Paul J.} and Ivan Ahel",
note = "Funding Information: We thank Friedrich Koch-Nolte (Universit{\"a}tsklinikum Hamburg-Eppendorf) for providing us with the mARTC2.2 expression construct, Helena Choltus (Universit{\'e} Blaise-Pascal) for assistance with plasmid preparation and initial expression trails, Ian Gibbs-Seymour (Sir William Dunn School of Pathology) for critical reading of the manuscript, and Diamond Light Source for access to beamlines I03, I04, I04-1, and I24 (proposal numbers mx12346 and mx18069), which contributed to the results presented here. Some NMR data were collected in the Institute for Genomic Biology Core on a 600-MHz NMR funded by NIH grant number S10-RR028833 . The work in I.A.{\textquoteright}s laboratory is funded by the Wellcome Trust (grant numbers 101794 and 210634 ) and Cancer Research United Kingdom (grant number C35050 / A22284 ), and the work in P.J.H.{\textquoteright}s laboratory was funded by the University of Illinois and NIH (grant number R21 CA212732 ). E.B. is funded by Kyoto Institute of Technology and Japan Society for the Promotion of Science and T.S. was supported by the Kao Corporation . Publisher Copyright: {\textcopyright} 2018 The Authors",
year = "2018",
month = dec,
day = "20",
doi = "10.1016/j.chembiol.2018.11.001",
language = "English (US)",
volume = "25",
pages = "1533--1546.e12",
journal = "Cell chemical biology",
issn = "2451-9456",
publisher = "Elsevier Inc.",
number = "12",
}