8T5C

Lassa GPC Trimer in complex with Fab 8.11G and nanobody D5

Summary for 8T5C

• Entry DOI: 10.2210/pdb8t5c/pdb
• EMDB information: 41048
• Descriptor: Glycoprotein G1, alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (14 entities in total)
• Functional Keywords: vaccine, gpc, gp1, gp2, viral protein-immune system complex, viral protein/immune system
• Biological source: Lassa virus Josiah; More
• Total number of polymer chains: 11
• Total formula weight: 216540.92

Authors

Gorman, J.,Kwong, P.D. (deposition date: 2023-06-13, release date: 2024-01-03, Last modification date: 2024-11-20)

Primary citation

Gorman, J.,Cheung, C.S.,Duan, Z.,Ou, L.,Wang, M.,Chen, X.,Cheng, C.,Biju, A.,Sun, Y.,Wang, P.,Yang, Y.,Zhang, B.,Boyington, J.C.,Bylund, T.,Charaf, S.,Chen, S.J.,Du, H.,Henry, A.R.,Liu, T.,Sarfo, E.K.,Schramm, C.A.,Shen, C.H.,Stephens, T.,Teng, I.T.,Todd, J.P.,Tsybovsky, Y.,Verardi, R.,Wang, D.,Wang, S.,Wang, Z.,Zheng, C.Y.,Zhou, T.,Douek, D.C.,Mascola, J.R.,Ho, D.D.,Ho, M.,Kwong, P.D.
Cleavage-intermediate Lassa virus trimer elicits neutralizing responses, identifies neutralizing nanobodies, and reveals an apex-situated site-of-vulnerability.
Nat Commun, 15:285-285, 2024

PubMed 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.

PubMed: 38177144
DOI: 10.1038/s41467-023-44534-y

Experimental method

ELECTRON MICROSCOPY (4.7 Å)