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

  • Author(s): 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
  • et al.
Abstract

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.

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