Journal
CELL REPORTS
Volume 24, Issue 2, Pages 441-452Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2018.06.041
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Funding
- National Key Plan for Scientific Research and Development of China [2016YFD0500307, 2016YFC1200902]
- National Natural Science Foundation of China [31470751, U1405228, 81530065, 81471929]
- Grand Challenges China [81661128042]
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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 beta 5-beta 6 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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