Viral macrodomains: a structural and evolutionary assessment of the pharmacological potential.

Open Biology
Johannes Gregor Matthias RackIvan Ahel

Abstract

Viral macrodomains possess the ability to counteract host ADP-ribosylation, a post-translational modification implicated in the creation of an antiviral environment via immune response regulation. This brought them into focus as promising therapeutic targets, albeit the close homology to some of the human macrodomains raised concerns regarding potential cross-reactivity and adverse effects for the host. Here, we evaluate the structure and function of the macrodomain of SARS-CoV-2, the causative agent of COVID-19. We show that it can antagonize ADP-ribosylation by PARP14, a cellular (ADP-ribosyl)transferase necessary for the restriction of coronaviral infections. Furthermore, our structural studies together with ligand modelling revealed the structural basis for poly(ADP-ribose) binding and hydrolysis, an emerging new aspect of viral macrodomain biology. These new insights were used in an extensive evolutionary analysis aimed at evaluating the druggability of viral macrodomains not only from the Coronaviridae but also Togaviridae and Iridoviridae genera (causing diseases such as Chikungunya and infectious spleen and kidney necrosis virus disease, respectively). We found that they contain conserved features, distinct from their h...Continue Reading

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Citations

Feb 14, 2021·Cells·Kerryanne CrawfordIvan Ahel
Apr 4, 2021·Cells·Ann-Katrin Hopp, Michael O Hottiger
May 29, 2021·Nature Communications·Dávid BajuszGyörgy M Keserű
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Jun 15, 2021·Molecular and Cellular Biology·Joyce van de Leemput, Zhe Han
Oct 10, 2021·Nature Communications·Ivo A HendriksMichael L Nielsen
Nov 18, 2021·Cell Reports Methods·Sven T SowaLari Lehtiö

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Methods Mentioned

BETA
Infection
ion-exchange chromatography
size exclusion chromatography
X-ray

Software Mentioned

Ligand Builder
Clustal Omega
S2
Mafft L - INS - I
Chimera
Phenix
Cel MacroD
CCP4i2
Cel
ConSurf

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