@article{a79117ad61144e22a207164d81cce8d5,
title = "Structural basis of broad ebolavirus neutralization by a human survivor antibody",
abstract = "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 GPCL) reveals that binding of the mAb structurally mimics the conserved interaction between the EBOV GP core and its glycan cap β17–β18 loop to inhibit infection. Both endosomal proteolysis of EBOV GP and binding of mAb FVM09 displace this loop, thereby increasing exposure of ADI-15946{\textquoteright}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.",
author = "West, {Brandyn R.} and Wec, {Anna Z.} and Moyer, {Crystal L.} and Fusco, {Marnie L.} and Ilinykh, {Philipp A.} and Kai Huang and Wirchnianski, {Ariel S.} and James, {Rebekah M.} and Herbert, {Andrew S.} and Sean Hui and Eileen Goodwin and Howell, {Katie A.} and Shweta Kailasan and Aman, {M. Javad} and Walker, {Laura M.} and Dye, {John M.} and Alexander Bukreyev and Kartik Chandran and Saphire, {Erica Ollmann}",
note = "Funding Information: X-ray diffraction data were collected at the Stanford Synchrotron Radiation Lightsource (SSRL), SLAC National Accelerator Laboratory. SSRL is supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract No. DE-AC02-76SF00515. The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research, and by the National Institutes of Health, National Institute of General Medical Sciences (including P41GM103393). Opinions, conclusions, interpretations, and recommendations are those of the authors and are not necessarily endorsed by the U.S. Army. The mention of trade names or commercial products does not constitute endorsement or recommendation for use by the Department of the Army or the Department of Defense. We acknowledge National Institutes of Health grants no. U19 AI109762 (E.O.S., K.C., J.M.D.), no. R01 AI132256 (K.C.), no. U19 AI109711 (A.B.), no. R01 AI132204 (E.O.S., M.J.A.) and no. R01 AI126587 (M.J.A.), the Defense Threat Reduction Agency HDTRA1-13-1-0034 (A.B.) and the Viral Hemorrhagic Fever Immunotherapeutic Consortium for support. This is manuscript number 29630 from The Scripps Research Institute. Publisher Copyright: {\textcopyright} 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2019",
month = mar,
day = "1",
doi = "10.1038/s41594-019-0191-4",
language = "English (US)",
volume = "26",
pages = "204--212",
journal = "Nature Structural and Molecular Biology",
issn = "1545-9993",
publisher = "Nature Publishing Group",
number = "3",
}