1. Structural Definition of a Neutralization-Sensitive Epitope on the MERS-CoV S1-NTD
- Author
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James D. Chappell, Barney S. Graham, Kizzmekia S. Corbett, Jason S. McLellan, Yi Zhang, Andrew B. Ward, Jesper Pallesen, Mark R. Denison, Kwanyee Leung, Nianshuang Wang, Charles A. Bowman, Osnat Rosen, Laura J. Stevens, Wei Shi, Robert N. Kirchdoerfer, Michelle M. Becker, Hannah L. Turner, and Lingshu Wang
- Subjects
0301 basic medicine ,Middle East respiratory syndrome coronavirus ,viruses ,Population ,Biology ,medicine.disease_cause ,Article ,General Biochemistry, Genetics and Molecular Biology ,Epitope ,Neutralization ,Epitopes ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,Neutralizing antibody ,education ,lcsh:QH301-705.5 ,Coronavirus ,education.field_of_study ,virus diseases ,Virology ,3. Good health ,respiratory tract diseases ,A-site ,030104 developmental biology ,lcsh:Biology (General) ,Middle East Respiratory Syndrome Coronavirus ,biology.protein ,Antibody ,030217 neurology & neurosurgery - Abstract
Summary: 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. : Wang et al. report the structural and functional characterization of the Middle East respiratory syndrome coronavirus (MERS-CoV)-neutralizing antibody G2. G2 recognizes a conserved epitope on the MERS-CoV S1 N-terminal domain (S1-NTD) and neutralizes MERS-CoV by interfering with binding to host receptor dipeptidyl peptidase-4 (DPP4). The findings are relevant for understanding the viral attachment mechanism and for the development of S1-NTD-based vaccines. Keywords: MERS-CoV, coronavirus, crystal structure, electron microscopy, DPP4, receptor-binding, membrane fusion
- Published
- 2019