Abstract
The newly emerging Middle East respiratory syndrome coronavirus (MERS-CoV) encodes the conserved macro domain within non-structural protein 3. However, the precise biochemical function and structure of the macro domain is unclear. Using differential scanning fluorimetry and isothermal titration calorimetry, we characterized the MERS-CoV macro domain as a more efficient adenosine diphosphate (ADP)-ribose binding module than macro domains from other CoVs. Furthermore, the crystal structure of the MERS-CoV macro domain was determined at 1.43-Å resolution in complex with ADP-ribose. Comparison of macro domains from MERS-CoV and other human CoVs revealed structural differences in the α1 helix alters how the conserved Asp-20 interacts with ADP-ribose and may explain the efficient binding of the MERS-CoV macro domain to ADP-ribose. This study provides structural and biophysical bases to further evaluate the role of the MERS-CoV macro domain in the host response via ADP-ribose binding but also as a potential target for drug design.
Highlights
The newly emerging Middle East respiratory syndrome coronavirus (MERS-CoV) encodes the conserved macro domain within non-structural protein 3
This study provides structural and biophysical bases to further evaluate the role of the MERS-CoV macro domain in the host response via adenosine diphosphate (ADP)-ribose binding and as a potential target for drug design
The significant increase in Tm suggests the interaction between the MERS-CoV macro domain and ADP-ribose
Summary
The newly emerging Middle East respiratory syndrome coronavirus (MERS-CoV) encodes the conserved macro domain within non-structural protein 3. This study provides structural and biophysical bases to further evaluate the role of the MERS-CoV macro domain in the host response via ADP-ribose binding and as a potential target for drug design. The macro domain of SARS-CoV NSP3 was previously reported to possess ADP-ribose and poly(ADP)-ribose binding ability, which suggests that the macro domain may regulate cellular proteins involved in an apoptotic pathway via poly(ADP)-ribosylation to mediate the host response to infection [36]. We investigated the MERS-CoV macro domain as an ADP-ribose binding module, with comparison to previously characterized viral macro domains. Our study may shed new light on structurally based design of novel antiviral drugs targeting viral macro domains
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