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TitleThe epitope arrangement on flavivirus particles contributes to Mab C10's extraordinary neutralization breadth across Zika and dengue viruses.
Journal, issue, pagesCell, Vol. 184, Issue 25, Page 6052-6066.e18, Year 2021
Publish dateDec 9, 2021
AuthorsArvind Sharma / Xiaokang Zhang / Wanwisa Dejnirattisai / Xinghong Dai / Danyang Gong / Wiyada Wongwiwat / Stéphane Duquerroy / Alexander Rouvinski / Marie-Christine Vaney / Pablo Guardado-Calvo / Ahmed Haouz / Patrick England / Ren Sun / Z Hong Zhou / Juthathip Mongkolsapaya / Gavin R Screaton / Felix A Rey /
PubMed AbstractThe human monoclonal antibody C10 exhibits extraordinary cross-reactivity, potently neutralizing Zika virus (ZIKV) and the four serotypes of dengue virus (DENV1-DENV4). Here we describe a comparative ...The human monoclonal antibody C10 exhibits extraordinary cross-reactivity, potently neutralizing Zika virus (ZIKV) and the four serotypes of dengue virus (DENV1-DENV4). Here we describe a comparative structure-function analysis of C10 bound to the envelope (E) protein dimers of the five viruses it neutralizes. We demonstrate that the C10 Fab has high affinity for ZIKV and DENV1 but not for DENV2, DENV3, and DENV4. We further show that the C10 interaction with the latter viruses requires an E protein conformational landscape that limits binding to only one of the three independent epitopes per virion. This limited affinity is nevertheless counterbalanced by the particle's icosahedral organization, which allows two different dimers to be reached by both Fab arms of a C10 immunoglobulin. The epitopes' geometric distribution thus confers C10 its exceptional neutralization breadth. Our results highlight the importance not only of paratope/epitope complementarity but also the topological distribution for epitope-focused vaccine design.
External linksCell / PubMed:34852239 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution2.1 - 3.6 Å
Structure data

EMDB-30465, PDB-7cth:
Cryo-EM structure of dengue virus serotype 2 in complex with the scFv fragment of the broadly neutralizing antibody EDE1 C10
Method: EM (single particle) / Resolution: 3.5 Å

PDB-7a3n:
Crystal structure of Zika virus envelope glycoprotein in complex with the Fab fragment of the broadly neutralizing human antibody EDE1 C10
Method: X-RAY DIFFRACTION / Resolution: 2.1 Å

PDB-7a3o:
Crystal structure of dengue 1 virus envelope glycoprotein in complex with the scFv fragment of the broadly neutralizing human antibody EDE1 C10
Method: X-RAY DIFFRACTION / Resolution: 2.8 Å

PDB-7a3p:
Crystal structure of dengue 3 virus envelope glycoprotein in complex with the scFv fragment of the broadly neutralizing human antibody EDE1 C10
Method: X-RAY DIFFRACTION / Resolution: 3.19 Å

PDB-7a3q:
Crystal structure of dengue 4 virus envelope glycoprotein in complex with the scFv fragment of the broadly neutralizing human antibody EDE1 C10
Method: X-RAY DIFFRACTION / Resolution: 2.7 Å

PDB-7a3r:
Crystal structure of dengue 1 virus envelope glycoprotein
Method: X-RAY DIFFRACTION / Resolution: 3.6 Å

PDB-7a3s:
Crystal structure of dengue 3 virus envelope glycoprotein
Method: X-RAY DIFFRACTION / Resolution: 2.8 Å

PDB-7a3t:
Crystal structure of dengue 3 virus envelope glycoprotein in complex with the Fab fragment of the broadly neutralizing human antibody EDE1 C8
Method: X-RAY DIFFRACTION / Resolution: 2.65 Å

PDB-7a3u:
Crystal structure of Zika virus envelope glycoprotein in complex with the divalent F(ab')2 fragment of the broadly neutralizing human antibody EDE1 C10
Method: X-RAY DIFFRACTION / Resolution: 3.0 Å

Chemicals

ChemComp-CA:
Unknown entry

ChemComp-HOH:
WATER / Water

ChemComp-GOL:
GLYCEROL / Glycerol

ChemComp-SO4:
SULFATE ION / Sulfate

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

ChemComp-3CX:
(2S)-3-(cyclohexylamino)-2-hydroxypropane-1-sulfonic acid

Source
  • dengue virus 2
  • homo sapiens (human)
  • zika virus
  • dengue virus 1
  • dengue virus 3
  • dengue virus 4
  • dengue virus 3 philippines/h87/1956
KeywordsVIRAL PROTEIN / FLAVIVIRUS / CLASS 2 FUSION PROTEIN / ANTIBODY / Fab / IMMUNOCOMPLEX / ZIKA / broadly neutralising antibody / DENGUE / F(ab')2 / VIRUS / Dengue virus / broadly neutralizing

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