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Title: Structural Definition of a Neutralization-Sensitive Epitope on the MERS-CoV S1-NTD

Abstract

Middle East respiratory syndrome coronavirus (MERS-CoV) emerged into the human population in 2012 and has caused substantial morbidity and mortality. Potently neutralizing antibodies targeting the receptor-binding domain (RBD) on MERS-CoV spike (S) protein have been characterized, but much less is known about antibodies targeting non-RBD epitopes. Here, we report the structural and functional characterization of G2, a neutralizing antibody targeting the MERS-CoV S1 N-terminal domain (S1-NTD). Structures of G2 alone and in complex with the MERS-CoV S1-NTD define a site of vulnerability comprising two loops, each of which contain a residue mutated in G2-escape variants. Cell-surface binding studies and in vitro competition experiments demonstrate that G2 strongly disrupts the attachment of MERS-CoV S to its receptor, dipeptidyl peptidase-4 (DPP4), with the inhibition requiring the native trimeric S conformation. These results advance our understanding of antibody-mediated neutralization of coronaviruses and should facilitate the development of immunotherapeutics and vaccines against MERS-CoV.

Authors:
; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
National Institutes of Health (NIH); National Institute of Allergy and Infectious Diseases (NIAID); USDOE Office of Science (SC), Biological and Environmental Research (BER)
OSTI Identifier:
1566185
Alternate Identifier(s):
OSTI ID: 1578239
Grant/Contract Number:  
R01AI127521; HHSN261200800001E; AC02-06CH11357
Resource Type:
Published Article
Journal Name:
Cell Reports
Additional Journal Information:
Journal Name: Cell Reports Journal Volume: 28 Journal Issue: 13; Journal ID: ISSN 2211-1247
Publisher:
Elsevier
Country of Publication:
Netherlands
Language:
English
Subject:
60 APPLIED LIFE SCIENCES

Citation Formats

Wang, Nianshuang, Rosen, Osnat, Wang, Lingshu, Turner, Hannah L., Stevens, Laura J., Corbett, Kizzmekia S., Bowman, Charles A., Pallesen, Jesper, Shi, Wei, Zhang, Yi, Leung, Kwanyee, Kirchdoerfer, Robert N., Becker, Michelle M., Denison, Mark R., Chappell, James D., Ward, Andrew B., Graham, Barney S., and McLellan, Jason S. Structural Definition of a Neutralization-Sensitive Epitope on the MERS-CoV S1-NTD. Netherlands: N. p., 2019. Web. doi:10.1016/j.celrep.2019.08.052.
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Wang, Nianshuang, Rosen, Osnat, Wang, Lingshu, Turner, Hannah L., Stevens, Laura J., Corbett, Kizzmekia S., Bowman, Charles A., Pallesen, Jesper, Shi, Wei, Zhang, Yi, Leung, Kwanyee, Kirchdoerfer, Robert N., Becker, Michelle M., Denison, Mark R., Chappell, James D., Ward, Andrew B., Graham, Barney S., & McLellan, Jason S. Structural Definition of a Neutralization-Sensitive Epitope on the MERS-CoV S1-NTD. Netherlands. https://doi.org/10.1016/j.celrep.2019.08.052
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Wang, Nianshuang, Rosen, Osnat, Wang, Lingshu, Turner, Hannah L., Stevens, Laura J., Corbett, Kizzmekia S., Bowman, Charles A., Pallesen, Jesper, Shi, Wei, Zhang, Yi, Leung, Kwanyee, Kirchdoerfer, Robert N., Becker, Michelle M., Denison, Mark R., Chappell, James D., Ward, Andrew B., Graham, Barney S., and McLellan, Jason S. Tue . "Structural Definition of a Neutralization-Sensitive Epitope on the MERS-CoV S1-NTD". Netherlands. https://doi.org/10.1016/j.celrep.2019.08.052.
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@article{osti_1566185,
title = {Structural Definition of a Neutralization-Sensitive Epitope on the MERS-CoV S1-NTD},
author = {Wang, Nianshuang and Rosen, Osnat and Wang, Lingshu and Turner, Hannah L. and Stevens, Laura J. and Corbett, Kizzmekia S. and Bowman, Charles A. and Pallesen, Jesper and Shi, Wei and Zhang, Yi and Leung, Kwanyee and Kirchdoerfer, Robert N. and Becker, Michelle M. and Denison, Mark R. and Chappell, James D. and Ward, Andrew B. and Graham, Barney S. and McLellan, Jason S.},
abstractNote = {Middle East respiratory syndrome coronavirus (MERS-CoV) emerged into the human population in 2012 and has caused substantial morbidity and mortality. Potently neutralizing antibodies targeting the receptor-binding domain (RBD) on MERS-CoV spike (S) protein have been characterized, but much less is known about antibodies targeting non-RBD epitopes. Here, we report the structural and functional characterization of G2, a neutralizing antibody targeting the MERS-CoV S1 N-terminal domain (S1-NTD). Structures of G2 alone and in complex with the MERS-CoV S1-NTD define a site of vulnerability comprising two loops, each of which contain a residue mutated in G2-escape variants. Cell-surface binding studies and in vitro competition experiments demonstrate that G2 strongly disrupts the attachment of MERS-CoV S to its receptor, dipeptidyl peptidase-4 (DPP4), with the inhibition requiring the native trimeric S conformation. These results advance our understanding of antibody-mediated neutralization of coronaviruses and should facilitate the development of immunotherapeutics and vaccines against MERS-CoV.},
doi = {10.1016/j.celrep.2019.08.052},
journal = {Cell Reports},
number = 13,
volume = 28,
place = {Netherlands},
year = {Tue Sep 24 00:00:00 EDT 2019},
month = {Tue Sep 24 00:00:00 EDT 2019}
}
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https://doi.org/10.1016/j.celrep.2019.08.052
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