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

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.

doi:10.1016/j.celrep.2019.08.052

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

Journal Article · Tue Sep 24 00:00:00 EDT 2019 · Cell Reports

DOI:https://doi.org/10.1016/j.celrep.2019.08.052· OSTI ID:1566185

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.

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.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: National Institutes of Health (NIH); National Institute of Allergy and Infectious Diseases (NIAID); USDOE Office of Science (SC), Biological and Environmental Research (BER)

Grant/Contract Number:: R01AI127521; HHSN261200800001E; AC02-06CH11357

OSTI ID:: 1566185

Alternate ID(s):: OSTI ID: 1578239

Journal Information:: Cell Reports, Journal Name: Cell Reports Vol. 28 Journal Issue: 13; ISSN 2211-1247

Publisher:: ElsevierCopyright Statement

Country of Publication:: Netherlands

Language:: English

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Cited by: 36 works

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