Abstract
Alphaviruses are (re-)emerging arboviruses of public health concern. The nsP3 gene product is one of the key players during viral replication. NsP3 comprises three domains: a macro domain, a zinc-binding domain and a hypervariable region. The macro domain is essential at both early and late stages of the replication cycle through ADP-ribose (ADPr) binding and de-ADP-ribosylation of host proteins. However, both its specific role and the precise molecular mechanism of de-ADP-ribosylation across specific viral families remains to be elucidated. Here we investigate by X-ray crystallography the mechanism of ADPr reactivity in the active site of Getah virus macro domain, which displays a peculiar substitution of one of the conserved residues in the catalytic loop. ADPr adopts distinct poses including a covalent bond between the C′′1 of the ADPr and a conserved Togaviridae-specific cysteine. These different poses observed for ADPr may represent snapshots of the de-ADP-ribosylation mechanism, highlighting residues to be further characterised.
| Original language | English |
|---|---|
| Article number | 14422 |
| Journal | Scientific Reports |
| Volume | 10 |
| Issue number | 1 |
| ISSN | 2045-2322 |
| DOIs | |
| Publication status | Published - 01.12.2020 |
Funding
We thank the European Synchrotron Radiation Facility (ESRF) and Synchrotron Soleil for beamtime allocation, and the staff of beamlines Proxima2, ID23-1 and ID30A-3 for assistance with data collection. This work was supported by the European Union Horizon 2020 Marie Skłodowska-Curie ETN “ANTIVIRALS” (Grant Agreement Number 642434) and by the French Infrastructure for Integrated Structural Biology (FRISBI) ANR-10-INSB-05-01. We thank Dr Karine Barral, Dr Sandrine Py and Dr Nicolas Papageorgiou for helpful discussions.
Research Areas and Centers
- Academic Focus: Center for Infection and Inflammation Research (ZIEL)
DFG Research Classification Scheme
- 2.11-01 Biochemistry
