Structural basis for Marburg virus neutralization by a cross-reactive human antibody.
The filoviruses, including Marburg and Ebola, express a single glycoprotein on their surface, termed GP, which is responsible for attachment and entry of target cells. Filovirus GPs differ by up to 70% in protein sequence, and no antibodies are yet described that cross-react among them. Here, we present the 3.6 Å crystal structure of Marburg virus GP in complex with a cross-reactive antibody from a human survivor, and a lower resolution structure of the antibody bound to Ebola virus GP. The antibody, MR78, recognizes a GP1 epitope conserved across the filovirus family, which likely represents the binding site of their NPC1 receptor. Indeed, MR78 blocks binding of the essential NPC1 domain C. These structures and additional small-angle X-ray scattering of mucin-containing MARV and EBOV GPs suggest why such antibodies were not previously elicited in studies of Ebola virus, and provide critical templates for development of immunotherapeutics and inhibitors of entry.
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA; Department of Virology, Faculty of Medicine, Kyushu University, Fukuoka, 812-8582, Japan.
Takao
T
Hashiguchi
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA.
Marnie L
ML
Fusco
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA.
Zachary A
ZA
Bornholdt
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA; Current address: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A1, Canada.
Jeffrey E
JE
Lee
Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN 37232, USA.
Andrew I
AI
Flyak
Division of Structural Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, 812-8582, Japan.
Rei
R
Matsuoka
Division of Structural Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, 812-8582, Japan.
Daisuke
D
Kohda
Department of Virology, Faculty of Medicine, Kyushu University, Fukuoka, 812-8582, Japan.
Yusuke
Y
Yanagi
Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720 USA.
Michal
M
Hammel
Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN 37232, USA; Vanderbilt Vaccine Center, Vanderbilt University, Nashville, TN 37232, USA.
James E
JE
Crowe
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA; The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA. Electronic address: erica@scripps.edu.
Erica Ollmann
EO
Saphire
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000378:metabolism; D057134:Antibodies, Neutralizing / Q000737:chemistry* / Q000276:immunology* / Q000302:isolation & purification / Q000378:metabolism; D000914:Antibodies, Viral / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D000936:Antigen-Antibody Complex / Q000737:chemistry; D002460:Cell Line; D003429:Cross Reactions; D018360:Crystallography, X-Ray; D004330:Drosophila; D029043:Ebolavirus / Q000737:chemistry; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry / Q000378:metabolism; D008379:Marburg Virus Disease / Q000276:immunology; D029024:Marburgvirus / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009077:Mucins / Q000737:chemistry; D016415:Sequence Alignment; D014759:Viral Envelope Proteins / Q000737:chemistry* / Q000378:metabolism
D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D000936:Antigen-Antibody Complex; C081324:GP-protein, Marburg virus; D007140:Immunoglobulin Fab Fragments; D009077:Mucins; D014759:Viral Envelope Proteins; C113189:envelope glycoprotein, Ebola virus