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Expression, Purification, Crystallization, and Enzyme Assays of Fumarylacetoacetate Hydrolase Domain-Containing Proteins
Published on: June 20, 2019
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(ADP-ribosyl)hydrolases: Structural Basis for Differential Substrate Recognition and Inhibition
Johannes Gregor Matthias Rack1, Antonio Ariza1, Bryon S Drown2
1Sir William Dunn School of Pathology, Oxford University, South Parks Road, Oxford OX1 3RE, UK.
Cell Chemical Biology
|November 26, 2018
Summary
ADP-(ribosyl)hydrolases (ARHs) reverse protein ADP-ribosylation. Structural analysis of ARH1 and ARH3 reveals distinct substrate binding but similar active sites, enabling targeted drug design.
Area of Science:
- Biochemistry
- Structural Biology
- Enzymology
Background:
- Protein ADP-ribosylation is a dynamic post-translational modification.
- ADP-(ribosyl)hydrolases (ARHs) are ancient enzymes that reverse this modification.
- ARHs are increasingly recognized for roles in cellular stress and tumor suppression.
Purpose of the Study:
- To perform a comprehensive structural analysis of ARH1 and ARH3.
- To understand the distinct substrate requirements and catalytic behaviors of ARH1 and ARH3.
- To elucidate the structural basis for selective ARH3 inhibition.
Main Methods:
- X-ray crystallography for structural analysis.
- Biochemical assays to determine enzyme-ligand interactions.
- Analysis of ADP-ribose analogues as inhibitors.
Main Results:
- ARH1 and ARH3 exhibit highly diverged binding of the adenosine ribose moiety.
- The active sites of ARH1 and ARH3 show close resemblance.
- The structural basis for selective inhibition of ARH3 by ADP-HPD and arginine-ADP-ribose was elucidated.
Conclusions:
- Structural insights into ARH1 and ARH3 enzyme-ligand interactions.
- Understanding the catalytic differences between ARH1 and ARH3.
- Providing tools for targeted drug design against ARHs.
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