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

King, Liam B. and Fusco, Marnie L. and Flyak, Andrew I. and Ilinykh, Philipp A. and Huang, Kai and Gunn, Bronwyn and Kirchdoerfer, Robert N. and Hastie, Kathryn M. and Sangha, Amandeep K. and Meiler, Jens and Alter, Galit and Bukreyev, Alexander and Crowe, James E., Jr. and Saphire, Erica Ollmann (2018) The Marburgvirus-Neutralizing Human Monoclonal Antibody MR191 Targets a Conserved Site to Block Virus Receptor Binding. Cell Host & Microbe, 23 (1). pp. 101-109. ISSN 1931-3128. https://resolver.caltech.edu/CaltechAUTHORS:20180125-082624363

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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.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1016/j.chom.2017.12.003DOIArticle
https://www.sciencedirect.com/science/article/pii/S1931312817305395PublisherArticle
ORCID:
AuthorORCID
Flyak, Andrew I.0000-0002-8722-479X
Bukreyev, Alexander0000-0002-0342-4824
Crowe, James E., Jr.0000-0002-0049-1079
Saphire, Erica Ollmann0000-0002-1206-7451
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.
Funders:
Funding AgencyGrant Number
NIHR01AI089498
NIHU19AI109762
NIHU19AI109762
NIHHDTRA1-13-1-0034
NIH1U19AI109711
NIHR21AI121799
Department of Energy (DOE)DE-AC02-06CH11357
Department of Energy (DOE)DE-AC02-76SF00515
NIHP41GM103393
Subject Keywords:marburgvirus; antibody; hemorrhagic fever; structural biology; Ravn virus; immunotherapeutic; structure; Marburg virus
Issue or Number:1
Record Number:CaltechAUTHORS:20180125-082624363
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20180125-082624363
Official Citation: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, The Marburgvirus-Neutralizing Human Monoclonal Antibody MR191 Targets a Conserved Site to Block Virus Receptor Binding, Cell Host & Microbe, Volume 23, Issue 1, 2018, Pages 101-109.e4, ISSN 1931-3128, https://doi.org/10.1016/j.chom.2017.12.003. (http://www.sciencedirect.com/science/article/pii/S1931312817305395)
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:84514
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:25 Jan 2018 17:10
Last Modified:09 Mar 2020 13:19

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