7UL7

Lineage I (Pinneo) Lassa virus glycoprotein bound to 18.5C-M30 Fab

Summary for 7UL7

• Entry DOI: 10.2210/pdb7ul7/pdb
• EMDB information: 26594
• Descriptor: Glycoprotein G1, 18.5C-M30 Fab Light Chain, 18.5C-M30 Fab Heavy Chain, ... (6 entities in total)
• Functional Keywords: glycoprotein, antibody, lassa virus, viral protein, viral protein-immune system complex, viral protein/immune system
• Biological source: Lassa mammarenavirus; More
• Total number of polymer chains: 12
• Total formula weight: 321425.13

Authors

Buck, T.K.,Enriquez, A.S.,Hastie, K.M. (deposition date: 2022-04-04, release date: 2022-06-15, Last modification date: 2024-11-13)

Primary citation

Buck, T.K.,Enriquez, A.S.,Schendel, S.L.,Zandonatti, M.A.,Harkins, S.S.,Li, H.,Moon-Walker, A.,Robinson, J.E.,Branco, L.M.,Garry, R.F.,Saphire, E.O.,Hastie, K.M.
Neutralizing Antibodies against Lassa Virus Lineage I.
Mbio, 13:e0127822-e0127822, 2022

PubMed Abstract: Lassa virus (LASV) is the causative agent of the deadly Lassa fever (LF). Seven distinct LASV lineages circulate through western Africa, among which lineage I (LI), the first to be identified, is particularly resistant to antibody neutralization. Lineage I LASV evades neutralization by half of known antibodies in the GPC-A antibody competition group and all but one of the antibodies in the GPC-B competition group. Here, we solve two cryo-electron microscopy (cryo-EM) structures of LI GP in complex with a GPC-A and a GPC-B antibody. We used complementary structural and biochemical techniques to identify single-amino-acid substitutions in LI that are responsible for immune evasion by each antibody group. Further, we show that LI infection is more dependent on the endosomal receptor lysosome-associated membrane protein 1 (LAMP1) for viral entry relative to LIV. In the absence of LAMP1, LI requires a more acidic fusion pH to initiate membrane fusion with the host cell relative to LIV. No vaccine or therapeutics are approved to prevent LASV infection or treat LF. All vaccine platforms currently under development present only the LIV GP sequence. However, our data suggest that the high genetic diversity of LASV may be problematic for designing both a broadly reactive immunogen and therapeutic. Here, we examine antibodies that are highly potent against LIV yet are ineffective against LI. By pinpointing LI mutations responsible for this decrease in antibody efficacy, we suggest that future vaccine platforms may need to incorporate specific LI-like mutations in order to generate a broadly neutralizing antibody response against all LASV lineages.

PubMed: 35730904
DOI: 10.1128/mbio.01278-22

Experimental method

ELECTRON MICROSCOPY (3.59 Å)