TY - JOUR
T1 - Structural Basis for Marburg Virus Neutralization by a Cross-Reactive Human Antibody
AU - Hashiguchi, Takao
AU - Fusco, Marnie L.
AU - Bornholdt, Zachary A.
AU - Lee, Jeffrey E.
AU - Flyak, Andrew I.
AU - Matsuoka, Rei
AU - Kohda, Daisuke
AU - Yanagi, Yusuke
AU - Hammel, Michal
AU - Crowe, James E.
AU - Saphire, Erica Ollmann
N1 - Funding Information:
We would like to thank Dr. Adrianna P.P. Zhang (TSRI) for help with data collection, Dr. Sebastien Igonet (TSRI and Calixar) for assistance with S2 cell expression, Dr. Kartik Chandran (Albert Einstein College of Medicine), C. Daniel Murin, and Dr. Andrew Ward (TSRI) for valuable discussions, and the beamline staff of Photon Factory (Tsukuba, Japan) for technical help during data collection. We thank NIAID CETR U19 AI109762 (E.O.S.), R01 AI089498 , and R21AI069347 (E.O.S.); Defense Threat Reduction Agency grant HDTRA1-13-1-0034 ; NIAID grant U19 AI109711 (J.E.C.); MEXT KAKENHI grant numbers 26713018 (T.H.) and 24115005 (Y.Y.); MEXT Platform for Drug Discovery Informatics and Structural Life Science (T.H.), JSPS Postdoctoral Fellowships (DC2 [R.M.], Research Abroad [T.H.]); a Research Fellowship of The Uehara Memorial Foundation (T.H.); an Investigators in the Pathogenesis of Infectious Disease award from the Burroughs Wellcome Fund (E.O.S.); and an NIH grant MINOS GM105404 (M.H.) for support. SIBYLS beamline efforts to combine SAXS and crystallography at the Advanced Light Source of Lawrence Berkeley National Laboratory are supported in part by US DOE program Integrated Diffraction Analysis Technologies (IDAT). This is manuscript # 28060 from The Scripps Research Institute.
Publisher Copyright:
© 2015 Elsevier Inc.
PY - 2015/2/26
Y1 - 2015/2/26
N2 - 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.
AB - 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.
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U2 - 10.1016/j.cell.2015.01.041
DO - 10.1016/j.cell.2015.01.041
M3 - Article
C2 - 25723165
AN - SCOPUS:84923350941
SN - 0092-8674
VL - 160
SP - 904
EP - 912
JO - Cell
JF - Cell
IS - 5
ER -
