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| Title | Structural development of the HIV-1 apex-directed PGT145-PGDM1400 antibody lineage. |
|---|---|
| Journal, issue, pages | Cell Rep, Vol. 44, Issue 1, Page 115223, Year 2025 |
| Publish date | Jan 28, 2025 |
Authors | Rosemarie D Mason / Baoshan Zhang / Nicholas C Morano / Chen-Hsiang Shen / Krisha McKee / Ashley Heimann / Renguang Du / Alexandra F Nazzari / Shelby Hodges / Tapan Kanai / Bob C Lin / Mark K Louder / Nicole A Doria-Rose / Tongqing Zhou / Lawrence Shapiro / Mario Roederer / Peter D Kwong / Jason Gorman / ![]() |
| 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 ...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. |
External links | Cell Rep / PubMed:39826122 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 3.41 - 3.44 Å |
| Structure data | EMDB-46478, PDB-9d1w: EMDB-46532, PDB-9d3d: |
| Chemicals | ![]() ChemComp-NAG: ![]() ChemComp-PO4: |
| Source |
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Keywords | VIRAL PROTEIN / HiV-1 / Vaccine / Fab / antibody / glycan / V2-apex |
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human immunodeficiency virus 1
homo sapiens (human)
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