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

• Published in: Cell Reports 2018-07, Vol.24 (2), p.441-452
• Main Authors: Zhang, Senyan, Zhou, Panpan, Wang, Pengfei, Li, Yangyang, Jiang, Liwei, Jia, Wenxu, Wang, Han, Fan, Angela, Wang, Dongli, Shi, Xuanling, Fang, Xianyang, Hammel, Michal, Wang, Shuying, Wang, Xinquan, Zhang, Linqi
• Format: Article
• Language: English
• Subjects: Antibodies, Neutralizing - metabolism; antibody epitope; Binding Sites; coronavirus; crystal structure; Epitopes - chemistry; Humans; Middle East respiratory syndrome; Middle East Respiratory Syndrome Coronavirus - chemistry; Middle East Respiratory Syndrome Coronavirus - genetics; Models, Molecular; Mutation - genetics; neutralizing antibody; Protein Binding; Protein Domains; Protein Multimerization; Spike Glycoprotein, Coronavirus - chemistry
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2018.06.041

The 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. [Display omitted] •MERS-4 binds RBD from the outside of the RBD–DPP4 binding interface•MERS-4 favors binding to the RBD in the “up” position in the S trimer•MERS-4 neutralizes MERS-CoV by indirect rather than direct competition with DPP4•MERS-4 is a valuable addition to the combined use of MERS-CoV antibodies Zhang et al. report the structural and functional analysis of the potent MERS-CoV 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.