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

Abstract

Graphical AbstractHighlights d The epitope for the neutralizing antibody G2 is confined to the apex of the MERS-CoV S1-NTD d G2 epitope is relatively well conserved d G2 IgG and Fab both neutralize pseudotyped and authentic MERS-CoV d G2 neutralizes by preventing the binding of DPP4 to trimeric S protein In Brief 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. SUMMARYMiddle 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.

COVID-19: Epidemiology, Evolution, and Cross-Disciplinary Perspectives

“…Previous studies showed that CoVs genomes display a high degree of plasticity in terms of gene content and recombination. Furthermore, the relatively large CoV genome increases the probabilities for adaptive mutations, with it being relative easy for the spike protein to exploit multiple cellular receptors for virus attachment and entry [52,[77][78][79]. These features are likely the cause of this alarming propensity of CoVs for host-species expansion.…”

Epitope-based chimeric peptide vaccine design against S, M and E proteins of SARS-CoV-2 etiologic agent of global pandemic COVID-19: anin silicoapproach

“…Therefore, other functional regions of the S glycoprotein can be important for developing effective prophylactic and therapeutic interventions against SARS-CoV-2 infection. Several mAbs targeting non-RBD regions, especially the NTD has recently been reported 13, 15 . The NTD is located on the side of the spike trimer and has not been observed to undergo any dynamic conformational changes 11 , and therefore, might play role in viral attachment, inducing neutralizing antibody responses and stimulates a protective cellular immunity against SARS-CoV 2, 6, 11 .…”

Structural Genomics of SARS-CoV-2 Indicates Evolutionary Conserved Functional Regions of Viral Proteins

“…Nevertheless, in the past two decades, a massive amount of work has been done to understand the molecular basis of the coronavirus evolution and infection, develop effective treatment in forms of both vaccines and antiviral drugs, and propose efficient measures for viral detection and prevention [9][10][11][12][13][14][15][16][17][18]. Structures of many individual proteins of SARS-CoV, MERS-CoV, and related coronaviruses, as well as their biological interactions with other viral and host proteins have been explored along with the experimental testing of the anti-viral properties of small-molecule inhibitors [16,[19][20][21][22][23][24][25][26][27][28][29][30][31].…”