期刊
NATURE STRUCTURAL & MOLECULAR BIOLOGY
卷 26, 期 3, 页码 204-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41594-019-0191-4
关键词
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资金
- U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-76SF00515]
- DOE Office of Biological and Environmental Research
- National Institutes of Health, National Institute of General Medical Sciences [P41GM103393]
- National Institutes of Health [U19 AI109762, R01 AI132256, U19 AI109711, R01 AI132204, R01 AI126587]
- Defense Threat Reduction Agency [HDTRA1-13-1-0034]
- Viral Hemorrhagic Fever Immunotherapeutic Consortium
- Scripps Research Institute [29630]
The structural features that govern broad-spectrum activity of broadly neutralizing anti-ebolavirus antibodies (Abs) outside of the internal fusion loop epitope are currently unknown. Here we describe the structure of a broadly neutralizing human monoclonal Ab (mAb), ADI-15946, which was identified in a human survivor of the 2013-2016 outbreak. The crystal structure of ADI-15946 in complex with cleaved Ebola virus glycoprotein (EBOV GP(CL)) reveals that binding of the mAb structurally mimics the conserved interaction between the EBOV GP core and its glycan cap beta 17-beta 18 loop to inhibit infection. Both endosomal proteolysis of EBOV GP and binding of mAb FVM09 displace this loop, thereby increasing exposure of ADI-15946's conserved epitope and enhancing neutralization. Our work also mapped the paratope of ADI-15946, thereby explaining reduced activity against Sudan virus, which enabled rational, structure-guided engineering to enhance binding and neutralization of Sudan virus while retaining the parental activity against EBOV and Bundibugyo virus.
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