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TitleStructural Definition of a Neutralization-Sensitive Epitope on the MERS-CoV S1-NTD.
Journal, issue, pagesCell Rep, Vol. 28, Issue 13, Page 3395-33405.e6, Year 2019
Publish dateSep 24, 2019
AuthorsNianshuang 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 /
PubMed AbstractMiddle 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 ...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.
External linksCell Rep / PubMed:31553909 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution2.1 - 24.0 Å
Structure data

EMDB-0486:
Negative stain EM map of MERS 2 in complex with G2 Fab
Method: EM (single particle) / Resolution: 24.0 Å

EMDB-20527: MERS S0 trimer in complex with antibody G2
PDB-6pz8: MERS S0 trimer in complex with variable domain of antibody G2
Method: EM (single particle) / Resolution: 4.19 Å

PDB-6pxg:
Crystal Structure of MERS-CoV neutralizing antibody G2 Fab
Method: X-RAY DIFFRACTION / Resolution: 2.1 Å

PDB-6pxh:
Crystal Structure of MERS-CoV S1-NTD bound with G2 Fab
Method: X-RAY DIFFRACTION / Resolution: 2.3 Å

Chemicals

ChemComp-HOH:
WATER / Water

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

ChemComp-SO4:
SULFATE ION / Sulfate

ChemComp-DHF:
DIHYDROFOLIC ACID / Dihydrofolic acid

Source
  • Middle East respiratory syndrome coronavirus
  • middle east respiratory syndrome-related coronavirus
  • mus musculus (house mouse)
KeywordsIMMUNE SYSTEM / antibody / fusion glycoprotein / IMMUNE SYSTEM/Viral protein / IMMUNE SYSTEM-Viral protein complex / VIRAL PROTEIN/IMMUNE SYSTEM / MERS-CoV / coronavirus / DPP4 / receptor-binding / membrane fusion / VIRAL PROTEIN-IMMUNE SYSTEM complex

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