(ADP-ribosyl)hydrolases: Structural Basis for Differential Substrate Recognition and Inhibition

Johannes Gregor Matthias Rack, Antonio Ariza, Bryon S. Drown, Callum Henfrey, Edward Bartlett, Tomohiro Shirai, Paul Hergenrother, Ivan Ahel

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1533-1546.e12
JournalCell chemical biology
Volume25
Issue number12
DOIs
StatePublished - Dec 20 2018

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Keywords

  • ADP-ribosylation
  • ADPRH
  • ADPRHL2
  • DNA damage
  • PARG
  • PARP
  • metalloenzyme

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

Cite this

Rack, J. G. M., Ariza, A., Drown, B. S., Henfrey, C., Bartlett, E., Shirai, T., Hergenrother, P., & Ahel, I. (2018). (ADP-ribosyl)hydrolases: Structural Basis for Differential Substrate Recognition and Inhibition. Cell chemical biology, 25(12), 1533-1546.e12. https://doi.org/10.1016/j.chembiol.2018.11.001