Revealing a MERS-CoV Vulnerability
Binding mechanism of the neutralizing antibody G2 to virus that causes Middle East Respiratory Syndrome (MERS-CoV). G2 (black ribbon structure) binds to the N-terminal domain (S1-NTD) of the S1 subunit (pink ribbon structure) of the MERS-CoV spike glycoprotein (white) protruding from MERS-CoV (gold). The antibody prevents the attachment of S1 to the dipeptidyl peptidase-4 (DPP4) receptor (red) on the host cell (green). [Image courtesy of Nianshuang Wang, The University of Texas at Austin.]
Researchers used X-ray macromolecular crystallography to derive the molecular structure and functional characterization of G2, a neutralizing antibody targeting the spike glycoprotein of the Middle East respiratory syndrome coronavirus (MERS-CoV). MERS-CoV was first identified in June 2012 and has an estimated case fatality rate of 36%.
The MERS-CoV spike protein comprises two subunits, S1 and S2. The S1 subunit mediates binding of the virus to the host cell receptor via its dipeptidyl peptidase-4 receptor (DPP4). Several neutralizing antibodies have been found that target either the N-terminal domain (NTD) or the receptor binding domain (RBD) of the S1 subunit, but those that target the former (S1-NTD) have not been well-characterized.
Crystal structures of G2, alone and in complex with its S1-NTD target, were obtained at the U.S. DOE’s Advanced Photon Source along with biochemical, biophysical, and cell-based assays. The data reveal a site of vulnerability on S1-NTD and point to a neutralization mechanism whereby G2 inhibits the attachment of the MERS-CoV spike protein to the DPP4 receptor, preventing infection of host cells.
The results increase the understanding of the viral attachment mechanism and may facilitate the development of S1-NTD-based vaccines against MERS-CoV.
Wang N, Rosen O, Wang L, et al. 2019. “Structural Definition of a Neutralization-Sensitive Epitope on the MERS-CoV S1-NTD.” Cell Rep. 28(13):3395-3405.e6. [DOI: 10.1016/j.celrep.2019.08.052]