EMD-26859
Ligand-free Lassa GPC Trimer with C3 Symmetry
EMD-26859
Single-particle5.7 Å
![EMD-26859](/em_static/emdb/emdb_no_image.png)
Map released: 10/05/2023
Last modified: 28/02/2024
Sample Organism:
Lassa virus Josiah
Sample: Lassa GPC trimer
Deposition Authors: Gorman J
,
Kwong PD
Sample: Lassa GPC trimer
Deposition Authors: Gorman J
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Cleavage-intermediate Lassa virus trimer elicits neutralizing responses, identifies neutralizing nanobodies, and reveals an apex-situated site-of-vulnerability.
Gorman J
,
Cheung CS,
Duan Z,
Ou L,
Wang M,
Chen X
,
Cheng C,
Biju A,
Sun Y,
Wang P
,
Yang Y,
Zhang B,
Boyington JC,
Bylund T,
Charaf S,
Chen SJ,
Du H,
Henry AR,
Liu T,
Sarfo EK
,
Schramm CA
,
Shen CH,
Stephens T,
Teng IT,
Todd JP,
Tsybovsky Y
,
Verardi R
,
Wang D
,
Wang S
,
Wang Z,
Zheng CY,
Zhou T
,
Douek DC
,
Mascola JR,
Ho DD,
Ho M
,
Kwong PD
(2024) Nat Commun , 15 , 285 - 285
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(2024) Nat Commun , 15 , 285 - 285
Abstract:
Lassa virus (LASV) infection is expanding outside its traditionally endemic areas in West Africa, posing a pandemic biothreat. LASV-neutralizing antibodies, moreover, have proven difficult to elicit. To gain insight into LASV neutralization, here we develop a prefusion-stabilized LASV glycoprotein trimer (GPC), pan it against phage libraries comprising single-domain antibodies (nanobodies) from shark and camel, and identify one, D5, which neutralizes LASV. Cryo-EM analyses reveal D5 to recognize a cleavage-dependent site-of-vulnerability at the trimer apex. The recognized site appears specific to GPC intermediates, with protomers lacking full cleavage between GP1 and GP2 subunits. Guinea pig immunizations with the prefusion-stabilized cleavage-intermediate LASV GPC, first as trimer and then as a nanoparticle, induce neutralizing responses, targeting multiple epitopes including that of D5; we identify a neutralizing antibody (GP23) from the immunized guinea pigs. Collectively, our findings define a prefusion-stabilized GPC trimer, reveal an apex-situated site-of-vulnerability, and demonstrate elicitation of LASV-neutralizing responses by a cleavage-intermediate LASV trimer.
Lassa virus (LASV) infection is expanding outside its traditionally endemic areas in West Africa, posing a pandemic biothreat. LASV-neutralizing antibodies, moreover, have proven difficult to elicit. To gain insight into LASV neutralization, here we develop a prefusion-stabilized LASV glycoprotein trimer (GPC), pan it against phage libraries comprising single-domain antibodies (nanobodies) from shark and camel, and identify one, D5, which neutralizes LASV. Cryo-EM analyses reveal D5 to recognize a cleavage-dependent site-of-vulnerability at the trimer apex. The recognized site appears specific to GPC intermediates, with protomers lacking full cleavage between GP1 and GP2 subunits. Guinea pig immunizations with the prefusion-stabilized cleavage-intermediate LASV GPC, first as trimer and then as a nanoparticle, induce neutralizing responses, targeting multiple epitopes including that of D5; we identify a neutralizing antibody (GP23) from the immunized guinea pigs. Collectively, our findings define a prefusion-stabilized GPC trimer, reveal an apex-situated site-of-vulnerability, and demonstrate elicitation of LASV-neutralizing responses by a cleavage-intermediate LASV trimer.