Wang N, Rosen O, Wang L, Turner HL, Stevens LJ, Corbett KS, Bowman CA, Pallesen J, Shi W, Zhang Y, Leung K, Kirchdoerfer RN, Becker MM, Denison MR, Chappell JD, Ward AB, Graham BS, McLellan JS. Structural Definition of a Neutralization-Sensitive Epitope on the MERS-CoV S1-NTD. Cell reports. 2019 Sep 24;28(28). 3395-3405.e6. PMID: 31553909 [PubMed]
Middle East respiratory syndrome coronavirus (MERS-CoV) emerged into the human population in 2012 and has caused substantial morbidity and mortality. Potently neutralizing antibodies targeting the receptor-binding domain (RBD) on MERS-CoV spike (S) protein have been characterized, but much less is known about antibodies targeting non-RBD epitopes. Here, we report the structural and functional characterization of G2, a neutralizing antibody targeting the MERS-CoV S1 N-terminal domain (S1-NTD). Structures of G2 alone and in complex with the MERS-CoV S1-NTD define a site of vulnerability comprising two loops, each of which contain a residue mutated in G2-escape variants. Cell-surface binding studies and in vitro competition experiments demonstrate that G2 strongly disrupts the attachment of MERS-CoV S to its receptor, dipeptidyl peptidase-4 (DPP4), with the inhibition requiring the native trimeric S conformation. These results advance our understanding of antibody-mediated neutralization of coronaviruses and should facilitate the development of immunotherapeutics and vaccines against MERS-CoV.