The Marburgvirus-Neutralizing Human Monoclonal Antibody MR191 Targets a Conserved Site to Block Virus Receptor Binding

Liam B. King, Marnie L. Fusco, Andrew I. Flyak, Philipp A. Ilinykh, Kai Huang, Bronwyn Gunn, Robert N. Kirchdoerfer, Kathryn M. Hastie, Amandeep K. Sangha, Jens Meiler, Galit Alter, Alexander Bukreyev, James E. Crowe, Erica Ollmann Saphire

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

Since their first identification 50 years ago, marburgviruses have emerged several times, with 83%–90% lethality in the largest outbreaks. Although no vaccines or therapeutics are available for human use, the human antibody MR191 provides complete protection in non-human primates when delivered several days after inoculation of a lethal marburgvirus dose. The detailed neutralization mechanism of MR191 remains outstanding. Here we present a 3.2 Å crystal structure of MR191 complexed with a trimeric marburgvirus surface glycoprotein (GP). MR191 neutralizes by occupying the conserved receptor-binding site and competing with the host receptor Niemann-Pick C1. The structure illuminates previously disordered regions of GP including the stalk, fusion loop, CX6CC switch, and an N-terminal region of GP2 that wraps about the outside of GP1 to anchor a marburgvirus-specific “wing” antibody epitope. Virus escape mutations mapped far outside the MR191 receptor-binding site footprint suggest a role for these other regions in the GP quaternary structure. Using structural analysis, King et al. demonstrate how the protective, potentially therapeutic, monoclonal antibody MR191 engages the marburgvirus glycoprotein receptor-binding site. The resulting complex is able to outcompete the host entry receptor NPC1 for viral neutralization. In addition, the structure illuminates previously disordered, functionally critical regions of the marburgvirus glycoprotein.

Original languageEnglish (US)
Pages (from-to)101-109.e4
JournalCell Host and Microbe
Volume23
Issue number1
DOIs
StatePublished - Jan 10 2018

Keywords

  • Marburg virus
  • Ravn virus
  • antibody
  • hemorrhagic fever
  • immunotherapeutic
  • marburgvirus
  • structural biology
  • structure

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Virology

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    King, L. B., Fusco, M. L., Flyak, A. I., Ilinykh, P. A., Huang, K., Gunn, B., Kirchdoerfer, R. N., Hastie, K. M., Sangha, A. K., Meiler, J., Alter, G., Bukreyev, A., Crowe, J. E., & Saphire, E. O. (2018). The Marburgvirus-Neutralizing Human Monoclonal Antibody MR191 Targets a Conserved Site to Block Virus Receptor Binding. Cell Host and Microbe, 23(1), 101-109.e4. https://doi.org/10.1016/j.chom.2017.12.003