6Z72

SARS-CoV-2 Macrodomain in complex with ADP-HPM

Summary for 6Z72

• Entry DOI: 10.2210/pdb6z72/pdb
• Descriptor: Replicase polyprotein 1ab, Adenosine Diphosphate (Hydroxymethyl)pyrrolidine monoalcohol, 1,2-ETHANEDIOL, ... (6 entities in total)
• Functional Keywords: viral macrodomain, adp-ribose binding module, adp-ribosylhydrolase, adp-ribosylation, viral protein, adp-hpm
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV)
• Total number of polymer chains: 4
• Total formula weight: 78680.38

Authors

Zorzini, V.,Rack, J.,Ahel, I. (deposition date: 2020-05-29, release date: 2020-12-02, Last modification date: 2024-01-24)

Primary citation

Rack, J.G.M.,Zorzini, V.,Zhu, Z.,Schuller, M.,Ahel, D.,Ahel, I.
Viral macrodomains: a structural and evolutionary assessment of the pharmacological potential.
Open Biology, 10:200237-200237, 2020

PubMed 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 but also and 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 human counterparts, which may be exploited during drug design.

PubMed: 33202171
DOI: 10.1098/rsob.200237

Experimental method

X-RAY DIFFRACTION (2.3 Å)