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TitleConvergence of a common solution for broad ebolavirus neutralization by glycan cap-directed human antibodies.
Journal, issue, pagesCell Rep, Vol. 35, Issue 2, Page 108984, Year 2021
Publish dateApr 13, 2021
AuthorsCharles D Murin / Pavlo Gilchuk / Philipp A Ilinykh / Kai Huang / Natalia Kuzmina / Xiaoli Shen / Jessica F Bruhn / Aubrey L Bryan / Edgar Davidson / Benjamin J Doranz / Lauren E Williamson / Jeffrey Copps / Tanwee Alkutkar / Andrew I Flyak / Alexander Bukreyev / James E Crowe / Andrew B Ward /
PubMed AbstractAntibodies that target the glycan cap epitope on the ebolavirus glycoprotein (GP) are common in the adaptive response of survivors. A subset is known to be broadly neutralizing, but the details of ...Antibodies that target the glycan cap epitope on the ebolavirus glycoprotein (GP) are common in the adaptive response of survivors. A subset is known to be broadly neutralizing, but the details of their epitopes and basis for neutralization are not well understood. Here, we present cryoelectron microscopy (cryo-EM) structures of diverse glycan cap antibodies that variably synergize with GP base-binding antibodies. These structures describe a conserved site of vulnerability that anchors the mucin-like domains (MLDs) to the glycan cap, which we call the MLD anchor and cradle. Antibodies that bind to the MLD cradle share common features, including use of IGHV1-69 and IGHJ6 germline genes, which exploit hydrophobic residues and form β-hairpin structures to mimic the MLD anchor, disrupt MLD attachment, destabilize GP quaternary structure, and block cleavage events required for receptor binding. Our results provide a molecular basis for ebolavirus neutralization by broadly reactive glycan cap antibodies.
External linksCell Rep / PubMed:33852862 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution3.002 - 9.9 Å
Structure data

EMDB-22839, PDB-7kej:
BDBV-289 bound to EBOV GPdMuc Makona
Method: EM (single particle) / Resolution: 3.8 Å

EMDB-22841: Bundibugyo virus GP (mucin deleted) bound to antibody Fab BDBV-43 and ADI-15878
PDB-7kew: Bundibugyo virus GP (mucin deleted) bound to antibody Fab BDBV-43
Method: EM (single particle) / Resolution: 4.16 Å

EMDB-22842, PDB-7kex:
Ebola virus GP (mucin deleted, Makona strain) bound to antibody Fab EBOV-293
Method: EM (single particle) / Resolution: 4.25 Å

EMDB-22847, PDB-7kf9:
Ebola virus GP (mucin deleted, Makona strain) bound to antibody Fab EBOV-296 and EBOV-515
Method: EM (single particle) / Resolution: 4.4 Å

EMDB-22848: Ebola virus GP (mucin deleted, Makona strain) bound to antibody Fab EBOV-442 and EBOV-515
PDB-7kfb: Ebola virus GP (mucin deleted, Makona strain) bound to antibody Fab EBOV-442
Method: EM (single particle) / Resolution: 3.9 Å

EMDB-22851: Bundibugyo virus GP (mucin deleted) bound to antibody Fab BDBV-329 and EBOV-515
PDB-7kfe: Bundibugyo virus GP (mucin deleted) bound to antibody Fab BDBV-329
Method: EM (single particle) / Resolution: 6.6 Å

EMDB-22852:
Ebola virus GP (mucin deleted, Makona strain) bound to antibody Fab EBOV-237 and EBOV-515
Method: EM (single particle) / Resolution: 9.9 Å

EMDB-22853: Ebola virus GP (mucin deleted, Makona strain) bound to antibody Fab EBOV-437 and EBOV-515
PDB-7kfh: Ebola virus GP (mucin deleted, Makona strain) bound to antibody Fab EBOV-437
Method: EM (single particle) / Resolution: 3.8 Å

PDB-7kfg:
Antibody Fab BDBV-289
Method: X-RAY DIFFRACTION / Resolution: 3.002 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

ChemComp-PEG:
DI(HYDROXYETHYL)ETHER

Source
  • homo sapiens (human)
  • ebola virus
  • zaire ebolavirus
  • bundibugyo ebolavirus
KeywordsVIRAL PROTEIN/Immune System / ebolavirus / glycan cap / antibody / broadly neutralizing / filovirus / VIRAL PROTEIN / VIRAL PROTEIN-Immune System complex / IMMUNE SYSTEM

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