Structural basis of broad ebolavirus neutralization by a human survivor antibody

Brandyn R. West, Anna Z. Wec, Crystal L. Moyer, Marnie L. Fusco, Philipp A. Ilinykh, Kai Huang, Ariel S. Wirchnianski, Rebekah M. James, Andrew S. Herbert, Sean Hui, Eileen Goodwin, Katie A. Howell, Shweta Kailasan, M. Javad Aman, Laura M. Walker, John M. Dye, Alexander Bukreyev, Kartik Chandran, Erica Ollmann Saphire

Research output: Contribution to journalArticle

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 GP CL ) 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’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.

Original languageEnglish (US)
Pages (from-to)204-212
Number of pages9
JournalNature Structural and Molecular Biology
Volume26
Issue number3
DOIs
StatePublished - Mar 1 2019

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Ebolavirus
Sudan
Viruses
Antibodies
Epitopes
Antibody Binding Sites
Neutralizing Antibodies
Proteolysis
Disease Outbreaks
Polysaccharides
Anti-Idiotypic Antibodies
Glycoproteins
Infection

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

Cite this

West, B. R., Wec, A. Z., Moyer, C. L., Fusco, M. L., Ilinykh, P. A., Huang, K., ... Saphire, E. O. (2019). Structural basis of broad ebolavirus neutralization by a human survivor antibody. Nature Structural and Molecular Biology, 26(3), 204-212. https://doi.org/10.1038/s41594-019-0191-4

Structural basis of broad ebolavirus neutralization by a human survivor antibody. / West, Brandyn R.; Wec, Anna Z.; Moyer, Crystal L.; Fusco, Marnie L.; Ilinykh, Philipp A.; Huang, Kai; Wirchnianski, Ariel S.; James, Rebekah M.; Herbert, Andrew S.; Hui, Sean; Goodwin, Eileen; Howell, Katie A.; Kailasan, Shweta; Aman, M. Javad; Walker, Laura M.; Dye, John M.; Bukreyev, Alexander; Chandran, Kartik; Saphire, Erica Ollmann.

In: Nature Structural and Molecular Biology, Vol. 26, No. 3, 01.03.2019, p. 204-212.

Research output: Contribution to journalArticle

West, BR, Wec, AZ, Moyer, CL, Fusco, ML, Ilinykh, PA, Huang, K, Wirchnianski, AS, James, RM, Herbert, AS, Hui, S, Goodwin, E, Howell, KA, Kailasan, S, Aman, MJ, Walker, LM, Dye, JM, Bukreyev, A, Chandran, K & Saphire, EO 2019, 'Structural basis of broad ebolavirus neutralization by a human survivor antibody', Nature Structural and Molecular Biology, vol. 26, no. 3, pp. 204-212. https://doi.org/10.1038/s41594-019-0191-4
West, Brandyn R. ; Wec, Anna Z. ; Moyer, Crystal L. ; Fusco, Marnie L. ; Ilinykh, Philipp A. ; Huang, Kai ; Wirchnianski, Ariel S. ; James, Rebekah M. ; Herbert, Andrew S. ; Hui, Sean ; Goodwin, Eileen ; Howell, Katie A. ; Kailasan, Shweta ; Aman, M. Javad ; Walker, Laura M. ; Dye, John M. ; Bukreyev, Alexander ; Chandran, Kartik ; Saphire, Erica Ollmann. / Structural basis of broad ebolavirus neutralization by a human survivor antibody. In: Nature Structural and Molecular Biology. 2019 ; Vol. 26, No. 3. pp. 204-212.
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