9D3D

Cryo-EM structure of PGT145 R100aS Fab bound to HIV-1 BG505 DS-SOSIP.664 Env trimer

Summary for 9D3D

• Entry DOI: 10.2210/pdb9d3d/pdb
• EMDB information: 46532
• Descriptor: HIV-1 BG505 DS-SOSIP gp120, alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-[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, beta-D-mannopyranose-(1-3)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (13 entities in total)
• Functional Keywords: hiv-1, vaccine, viral protein, fab, antibody, glycan, v2-apex
• Biological source: Human immunodeficiency virus 1; More
• Total number of polymer chains: 8
• Total formula weight: 290008.45

Authors

Hodges, S.,Morano, N.C.,Shapiro, L.,Kwong, P.D.,Gorman, J. (deposition date: 2024-08-09, release date: 2024-12-25, Last modification date: 2025-02-05)

Primary citation

Mason, R.D.,Zhang, B.,Morano, N.C.,Shen, C.H.,McKee, K.,Heimann, A.,Du, R.,Nazzari, A.F.,Hodges, S.,Kanai, T.,Lin, B.C.,Louder, M.K.,Doria-Rose, N.A.,Zhou, T.,Shapiro, L.,Roederer, M.,Kwong, P.D.,Gorman, J.
Structural development of the HIV-1 apex-directed PGT145-PGDM1400 antibody lineage.
Cell Rep, 44:115223-115223, 2025

PubMed Abstract: Broadly neutralizing antibodies (bNAbs) targeting the apex of the HIV-1-envelope (Env) trimer comprise the most potent category of HIV-1 bNAbs and have emerged as promising therapeutics. Here, we investigate the development of the HIV-1 apex-directed PGT145-PGDM1400 antibody lineage and report cryo-EM structures at 3.4 Å resolution of PGDM1400 and of an improved PGT145 variant (PGT145-R100aS), each bound to the BG505 Env trimer. Cross-species-based engineering improves PGT145 IC breadth to near that of PGDM1400. Despite similar breadth and potency, the two antibodies differ in their residue-level interactions with important apex features, including N160 glycans and apex cavity, with residue 100i of PGT145 (sulfated tyrosine) penetrating ∼7 Å farther than residue 100i of PGDM1400 (aspartic acid). While apex-directed bNAbs from other donors use maturation pathways that often converge on analogous residue-level recognition, our results demonstrate that divergent residue-level recognition can occur within the same lineage, thereby enabling improved coverage of escape variants.

PubMed: 39826122
DOI: 10.1016/j.celrep.2024.115223

Experimental method

ELECTRON MICROSCOPY (3.41 Å)