期刊
CELL
卷 183, 期 4, 页码 1013-+出版社
CELL PRESS
DOI: 10.1016/j.cell.2020.09.035
关键词
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资金
- Beijing Advanced Innovation Center for Genomics at Peking University
- Ministry of Science and Technology of the People's Republic of China [2020YFC0848700]
- Beijing Municipal Commission of Science and Technology [Z201100005420018]
- Fundamental Research Funds for the Central Universities [A20ZX00846]
- National Mega projects of China for Major Infectious Diseases [2017ZX10304402]
- CAMS initiative for Innovative Medicine of China [2016-I2M-2-006]
- National Key Research and Development Program of China [2017YFA0505200]
- National Science Foundation of China [31822014]
- Qidong-SLS Innovation Fund
Understanding how potent neutralizing antibodies (NAbs) inhibitSARS-CoV-2 is critical for effective therapeutic development. We previously described BD-368-2, a SARS-CoV-2 NAb with high potency; however, its neutralization mechanismis largely unknown. Here, we report the 3.5-angstrom cryo-EM structure of BD-368-2/trimeric-spike complex, revealing that BD-368-2 fully blocks ACE2 recognition by occupying all three receptor-binding domains (RBDs) simultaneously, regardless of their up'' or down'' conformations. Also, BD-368-2 treats infected adult hamsters at low dosages and at various administering windows, in contrast to placebo hamsters that manifested severe interstitial pneumonia. Moreover, BD-368-2's epitope completely avoids the common binding site of VH3-53/VH3-66 recurrent NAbs, evidenced by tripartite co-crystal structures with RBDs. Pairing BD-368-2 with a potent recurrent NAb neutralizes SARS-CoV-2 pseudovirus at pM level and rescues mutation-induced neutralization escapes. Together, our results rationalized a new RBD epitope that leads to high neutralization potency and demonstrated BD-368-2's therapeutic potential in treating COVID-19.
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