CaltechAUTHORS
Published January 10, 2018 | Version Supplemental Material
Journal Article Open

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

Creators

  • 1. ROR icon Scripps Research Institute
  • 2. ROR icon Vanderbilt University Medical Center
  • 3. ROR icon The University of Texas Medical Branch at Galveston
  • 4. ROR icon Massachusetts General Hospital
  • 5. ROR icon Vanderbilt University

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, CX_6CC 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.

Additional Information

© 2017 Elsevier Inc. Received 31 July 2017, Revised 28 October 2017, Accepted 8 December 2017, Available online 10 January 2018. We thank Drs. Zachary Bornholdt and Larry Zeitlin of Mapp Biopharmaceutical for the gift of MR191, MR82, and MR78 IgG and for helpful discussions. R01AI089498 and U19AI109762 (E.O.S.), U19AI109762 (G.A.), HDTRA1-13-1-0034 (J.E.C.), NIH1U19AI109711 (J.E.C. and A.B.), and R21AI121799 (J.M.) provided financial support. We thank the staff of beamline 23-ID-D of the Advanced Photon Source and beamline 12-2 of the Stanford Synchrotron Radiation Lightsource for assistance with data collection. This research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract no. DE-AC02-06CH11357. Use of the Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, 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 NIH, National Institute of General Medical Sciences (including P41GM103393). Coordinates and structure factors for the MR191-RAVV GP complex have been deposited into the Protein Data Bank under accession number PDB: 6BP2. In light of the higher-resolution map described here, the earlier model of RAVV GP (PDB: 3X2D) has been updated and is available at PDB: 5UQY. This is manuscript number 29544 from The Scripps Research Institute. Author Contributions: Conceptualization, L.B.K., M.L.F., A.B., J.E.C., and E.O.S.; Methodology, L.B.K., M.L.F., B.G., R.N.K., and A.K.S.; Validation, R.N.K. and K.M.H.; Investigation, L.B.K., M.L.F., A.I.F., P.A.I., K.H., B.G., and A.K.S.; Resources, J.E.C. and E.O.S.; Writing – Original Draft, L.B.K. and E.O.S.; Writing – Review & Editing, all authors; Visualization, L.B.K. and E.O.S.; Supervision, J.M., G.A., A.B., J.E.C., and E.O.S.; Project Administration, J.E.C., A.B., and E.O.S.; Funding Acquisition, J.M., G.A., A.B., J.E.C., and E.O.S. Declaration of Interests: J.E.C., A.B., A.I.F., and P.A.I. are listed as co-inventors for a patent submitted, which includes in part claims relating to MR191. The MR191 antibody has been licensed by Vanderbilt University to a commercial partner.

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Additional details

Identifiers

Eprint ID
84514
Resolver ID
CaltechAUTHORS:20180125-082624363

Funding

NIH
R01AI089498
NIH
U19AI109762
NIH
U19AI109762
NIH
HDTRA1-13-1-0034
NIH
1U19AI109711
NIH
R21AI121799
Department of Energy (DOE)
DE-AC02-06CH11357
Department of Energy (DOE)
DE-AC02-76SF00515
NIH
P41GM103393

Dates

Created
2018-01-25
Created from EPrint's datestamp field
Updated
2021-11-15
Created from EPrint's last_modified field