ADP-ribose and analogues bound to the deMARylating macrodomain from the bat coronavirus HKU4

Macrodomains are proteins that recognize and hydrolyze ADP ribose (ADPR) modifications of intracellular proteins. Macrodomains are implicated in viral genome replication and interference with host cell immune responses. They are important to the infectious cycle of Coronaviridae and Togaviridae viru...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2021-01, Vol.118 (2), p.1-11
Main Authors: Hammond, Robert G., Schormann, Norbert, McPherson, Robert Lyle, Leung, Anthony K. L., Deivanayagam, Champion C. S., Johnson, Margaret A.
Format: Article
Language:English
Subjects:
Adenosine Diphosphate Ribose - chemistry
Animals
Binding Sites
Biological Sciences
Chiroptera
Coronavirus - enzymology
Coronavirus - genetics
Crystallography, X-Ray
Hydrolysis
Pyrophosphatases - chemistry
Pyrophosphatases - genetics
Viral Nonstructural Proteins - chemistry
Viral Nonstructural Proteins - genetics
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Summary:Macrodomains are proteins that recognize and hydrolyze ADP ribose (ADPR) modifications of intracellular proteins. Macrodomains are implicated in viral genome replication and interference with host cell immune responses. They are important to the infectious cycle of Coronaviridae and Togaviridae viruses. We describe crystal structures of the conserved macrodomain from the bat coronavirus (CoV) HKU4 in complex with ligands. The structures reveal a binding cavity that accommodates ADPR and analogs via local structural changes within the pocket. Using a radioactive assay, we present evidence of mono-ADPR (MAR) hydrolase activity. In silico analysis presents further evidence on recognition of the ADPR modification for hydrolysis. Mutational analysis of residues within the binding pocket resulted in diminished enzymatic activity and binding affinity. We conclude that the common structural features observed in the macrodomain in a bat CoV contribute to a conserved function that can be extended to other known macrodomains.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.2004500118