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TitleDelineating the mechanism of anti-Lassa virus GPC-A neutralizing antibodies.
Journal, issue, pagesCell Rep, Vol. 39, Issue 8, Page 110841, Year 2022
Publish dateMay 24, 2022
AuthorsAdrian S Enriquez / Tierra K Buck / Haoyang Li / Michael J Norris / Alex Moon-Walker / Michelle A Zandonatti / Stephanie S Harkins / James E Robinson / Luis M Branco / Robert F Garry / Erica Ollmann Saphire / Kathryn M Hastie /
PubMed AbstractLassa virus (LASV) is the etiologic agent of Lassa Fever, a hemorrhagic disease that is endemic to West Africa. During LASV infection, LASV glycoprotein (GP) engages with multiple host receptors for ...Lassa virus (LASV) is the etiologic agent of Lassa Fever, a hemorrhagic disease that is endemic to West Africa. During LASV infection, LASV glycoprotein (GP) engages with multiple host receptors for cell entry. Neutralizing antibodies against GP are rare and principally target quaternary epitopes displayed only on the metastable, pre-fusion conformation of GP. Currently, the structural features of the neutralizing GPC-A antibody competition group are understudied. Structures of two GPC-A antibodies presented here demonstrate that they bind the side of the pre-fusion GP trimer, bridging the GP1 and GP2 subunits. Complementary biochemical analyses indicate that antibody 25.10C, which is broadly specific, neutralizes by inhibiting binding of the endosomal receptor LAMP1 and also by blocking membrane fusion. The other GPC-A antibody, 36.1F, which is lineage-specific, prevents LAMP1 association only. These data illuminate a site of vulnerability on LASV GP and will guide efforts to elicit broadly reactive therapeutics and vaccines.
External linksCell Rep / PubMed:35613585 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution2.57 - 2.8 Å
Structure data

EMDB-26195, PDB-7tyv:
Structure of Lassa Virus glycoprotein (Josiah) bound to Fab 25.10C
Method: EM (single particle) / Resolution: 2.8 Å

PDB-7s8g:
Structure of anti-LASV Fab 25.10C with FNQI mutation
Method: X-RAY DIFFRACTION / Resolution: 2.57 Å

PDB-7s8h:
Structure of Lassa virus glycoprotein bound to Fab 18.5C and Fab 36.1F
Method: X-RAY DIFFRACTION / Resolution: 2.7 Å

Chemicals

ChemComp-HOH:
WATER / Water

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

Source
  • homo sapiens (human)
  • lassa virus
KeywordsANTIVIRAL PROTEIN / IMMUNE SYSTEM / anti-LASV Fab / elbow mutation / domain swap / VIRAL PROTEIN/IMMUNE SYSTEM / Lassa virus / pre-fusion glycoprotein / Fab fragment / antibody-mediated neutralization / VIRAL PROTEIN / VIRAL PROTEIN-IMMUNE SYSTEM complex / Surface glycoprotein / antibody Fab fragment / epitope-mapping

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