8P0E

Rubella virus p150 macro domain in complex with ADP-ribose

Summary for 8P0E

• Entry DOI: 10.2210/pdb8p0e/pdb
• Related: 8P0C
• Descriptor: Non-structural polyprotein p200, ADENOSINE-5-DIPHOSPHORIBOSE (3 entities in total)
• Functional Keywords: macro domain, a1pp domain, adp-ribosylhydrolase, adp-ribose, hydrolase
• Biological source: Rubella virus
• Total number of polymer chains: 2
• Total formula weight: 41020.28

Authors

Stoll, G.A.,Modis, Y. (deposition date: 2023-05-10, release date: 2024-01-17, Last modification date: 2024-03-06)

Primary citation

Stoll, G.A.,Nikolopoulos, N.,Zhai, H.,Zhang, L.,Douse, C.H.,Modis, Y.
Crystal structure and biochemical activity of the macrodomain from rubella virus p150.
J.Virol., 98:e0177723-e0177723, 2024

PubMed Abstract: Rubella virus encodes a nonstructural polyprotein with RNA polymerase, methyltransferase, and papain-like cysteine protease activities, along with a putative macrodomain of unknown function. Macrodomains bind ADP-ribose adducts, a post-translational modification that plays a key role in host-virus conflicts. Some macrodomains can also remove the mono-ADP-ribose adduct or degrade poly-ADP-ribose chains. Here, we report high-resolution crystal structures of the macrodomain from rubella virus nonstructural protein p150, with and without ADP-ribose binding. The overall fold is most similar to macroD-type macrodomains from various nonviral species. The specific composition and structure of the residues that coordinate ADP-ribose in the rubella virus macrodomain are most similar to those of macrodomains from alphaviruses. Isothermal calorimetry shows that the rubella virus macrodomain binds ADP-ribose in solution. Enzyme assays show that the rubella virus macrodomain can hydrolyze both mono- and poly-ADP-ribose adducts. Site-directed mutagenesis identifies Asn39 and Cys49 required for mono-ADP-ribosylhydrolase (de-MARylation) activity.IMPORTANCERubella virus remains a global health threat. Rubella infections during pregnancy can cause serious congenital pathology, for which no antiviral treatments are available. Our work demonstrates that, like alpha- and coronaviruses, rubiviruses encode a mono-ADP-ribosylhydrolase with a structurally conserved macrodomain fold to counteract MARylation by poly (ADP-ribose) polymerases (PARPs) in the host innate immune response. Our structural data will guide future efforts to develop novel antiviral therapeutics against rubella or infections with related viruses.

PubMed: 38289106
DOI: 10.1128/jvi.01777-23

Experimental method

X-RAY DIFFRACTION (1.59 Å)