8JTD

BJOX2000.664 trimer in complex with Fab fragment of broadly neutralizing HIV antibody PGT145

Summary for 8JTD

• Entry DOI: 10.2210/pdb8jtd/pdb
• EMDB information: 36630 36641
• Descriptor: gp120 protein of HIV Envelope trimer, alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]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, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (11 entities in total)
• Functional Keywords: hiv, envelope trimer, broadly neutralizing antibody, pgt145, cryo-em, viral protein
• Biological source: Human immunodeficiency virus 1; More
• Total number of polymer chains: 8
• Total formula weight: 292018.97

Authors

Chatterjee, A.,Chen, C.,Lee, K.,Mangala Prasad, V. (deposition date: 2023-06-21, release date: 2023-10-25, Last modification date: 2024-10-30)

Primary citation

Hodge, E.A.,Chatterjee, A.,Chen, C.,Naika, G.S.,Laohajaratsang, M.,Mangala Prasad, V.,Lee, K.K.
An HIV-1 broadly neutralizing antibody overcomes structural and dynamic variation through highly focused epitope targeting.
Npj Viruses, 1:2-2, 2023

PubMed Abstract: The existence of broadly cross-reactive antibodies that can neutralize diverse HIV-1 isolates (bnAbs) has been appreciated for more than a decade. Many high-resolution structures of bnAbs, typically with one or two well-characterized HIV-1 Env glycoprotein trimers, have been reported. However, an understanding of how such antibodies grapple with variability in their antigenic targets across diverse viral isolates has remained elusive. To achieve such an understanding requires first characterizing the extent of structural and antigenic variation embodied in Env, and then identifying how a bnAb overcomes that variation at a structural level. Here, using hydrogen/deuterium-exchange mass spectrometry (HDX-MS) and quantitative measurements of antibody binding kinetics, we show that variation in structural ordering in the V1/V2 apex of Env across a globally representative panel of HIV-1 isolates has a marked effect on antibody association rates and affinities. We also report cryo-EM reconstructions of the apex-targeting PGT145 bnAb bound to two divergent Env that exhibit different degrees of structural dynamics throughout the trimer structures. Parallel HDX-MS experiments demonstrate that PGT145 bnAb has an exquisitely focused footprint at the trimer apex where binding did not yield allosteric changes throughout the rest of the structure. These results demonstrate that structural dynamics are a cryptic determinant of antigenicity, and mature antibodies that have achieved breadth and potency in some cases are able to achieve their broad cross-reactivity by "threading the needle" and binding in a highly focused fashion, thus evading and overcoming the variable properties found in Env from divergent isolates.

PubMed: 38665238
DOI: 10.1038/s44298-023-00002-4

Experimental method

ELECTRON MICROSCOPY (4.9 Å)