@article{1356e9e7006740a0982189993f41897b,
title = "The Marburgvirus-Neutralizing Human Monoclonal Antibody MR191 Targets a Conserved Site to Block Virus Receptor Binding",
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 {\AA} 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.",
keywords = "Marburg virus, Ravn virus, antibody, hemorrhagic fever, immunotherapeutic, marburgvirus, structural biology, structure",
author = "King, {Liam B.} and Fusco, {Marnie L.} and Flyak, {Andrew I.} and Ilinykh, {Philipp A.} and Kai Huang and Bronwyn Gunn and Kirchdoerfer, {Robert N.} and Hastie, {Kathryn M.} and Sangha, {Amandeep K.} and Jens Meiler and Galit Alter and Alexander Bukreyev and Crowe, {James E.} and Saphire, {Erica Ollmann}",
note = "Funding Information: 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.), NIH 1U19AI109711 (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. Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",
year = "2018",
month = jan,
day = "10",
doi = "10.1016/j.chom.2017.12.003",
language = "English (US)",
volume = "23",
pages = "101--109.e4",
journal = "Cell Host and Microbe",
issn = "1931-3128",
publisher = "Cell Press",
number = "1",
}