Structural Definition of a Unique Neutralization Epitope on the Receptor-Binding Domain of MERS-CoV Spike Glycoprotein

Senyan Zhang,Panpan Zhou,Pengfei Wang,Yangyang Li,Liwei Jiang,Wenxu Jia,Han Wang,Angela Fan,Dongli Wang,Xuanling Shi,Xianyang Fang,Michal Hammel,Shuying Wang,Xinquan Wang,Linqi Zhang

doi:10.1016/j.celrep.2018.06.041

Abstract

SummaryThe major mechanism of antibody-mediated neutralization of the Middle East respiratory syndrome coronavirus (MERS-CoV) involves competition with the cellular receptor dipeptidyl peptidase 4 (DPP4) for binding to the receptor-binding domain (RBD) of the spike (S) glycoprotein. Here, we report a unique epitope and unusual neutralizing mechanism of the isolated human antibody MERS-4. Structurally, MERS-4 approached the RBD from the outside of the RBD-DPP4 binding interface. Such binding resulted in the folding of the β5-β6 loop toward a shallow groove on the RBD interface critical for accommodating DPP4. The key residues for binding are identified through site-directed mutagenesis. Structural modeling revealed that MERS-4 binds to RBD only in the “up” position in the S trimer. Furthermore, MERS-4 demonstrated synergy with several reported antibodies. These results indicate that MERS-4 neutralizes MERS-CoV by indirect rather than direct competition with DPP4. This mechanism provides a valuable addition for the combined use of antibodies against MERS-CoV infection.

Highlights

The 2012 emergence of the Middle East respiratory syndrome coronavirus (MERS-CoV) in Saudi Arabia was the second major introduction of a highly pathogenic coronavirus into the human population since the outbreak of SARS-CoV in China in 2003 (Assiri et al, 2013; Zaki et al, 2012)
MERS-4 approached the receptor-binding domain (RBD) from the outside of the RBD-dipeptidyl peptidase 4 (DPP4) binding interface
Such binding resulted in the folding of the b5-b6 loop toward a shallow groove on the RBD interface critical for accommodating DPP4

Summary

Graphical Abstract

Zhang et al report the structural and functional analysis of the potent MERSCoV neutralizing antibody MERS-4. MERS-4 recognizes a unique epitope and indirectly disrupts interaction between the receptor binding domain and the receptor DPP4. This mechanism provides a valuable addition for the combined use of antibodies against MERS-CoV infection. Highlights d MERS-4 binds RBD from the outside of the RBD–DPP4 binding interface. 2018, Cell Reports 24, 441–452 July 10, 2018 a 2018 The Authors.

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