Structural Definition of a Neutralization-Sensitive Epitope on the MERS-CoV S1-NTD
Nianshuang Wang,
Osnat Rosen,
Lingshu Wang,
Hannah L. Turner,
Laura J. Stevens,
Kizzmekia S. Corbett,
Charles A. Bowman,
Jesper Pallesen,
Wei Shi,
Yi Zhang,
Kwanyee Leung,
Robert N. Kirchdoerfer,
Michelle M. Becker,
Mark R. Denison,
James D. Chappell,
Andrew B. Ward,
Barney S. Graham,
Jason S. McLellan
Affiliations
Nianshuang Wang
Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA
Osnat Rosen
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA
Lingshu Wang
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA
Hannah L. Turner
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
Laura J. Stevens
Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
Kizzmekia S. Corbett
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA
Charles A. Bowman
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
Jesper Pallesen
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
Wei Shi
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA
Yi Zhang
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA
Kwanyee Leung
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA
Robert N. Kirchdoerfer
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
Michelle M. Becker
Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
Mark R. Denison
Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
James D. Chappell
Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
Andrew B. Ward
Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
Barney S. Graham
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA
Jason S. McLellan
Department of Molecular Biosciences, The University of Texas at Austin, Austin, TX 78712, USA; Corresponding author
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
