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Conformational and Structural Features of HIV-1 gp120 Underlying Dual Receptor Antagonism by the Cross-Reactive Neutralizing Antibody, m18
Journal article   Open access   Peer reviewed

Conformational and Structural Features of HIV-1 gp120 Underlying Dual Receptor Antagonism by the Cross-Reactive Neutralizing Antibody, m18

Syna Kuriakose Gift, Isaac J Zentner, Arne Schön, Karyn McFadden, M Umashankara, Srivats Rajagopal, Mark Contarino, Caitlin Duffy, Joel R Courter, Mei-Yun Zhang, …
Biochemistry (Easton), v 50(14), pp 2756-2768
12 Apr 2011
DOI: https://doi.org/10.1021/bi101160r
PMID: 21351734
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://doi.org/10.1021/bi101160rView
Published, Version of Record (VoR) Open

Abstract

We investigated the interaction between the cross-reactive HIV-1 neutralizing human monoclonal antibody m18 with HIV-1 YU-2 gp120 in order to understand how this antibody inhibits viral entry into cells. M18 binds to gp120 with high affinity (K D ≈ 5 nM) as measured by surface plasmon resonance (SPR) and isothermal titration calorimetry (ITC). SPR analysis further showed that m18 inhibits gp120 interactions with both soluble CD4 as well as CD4-induced antibodies that have epitopes overlapping the coreceptor binding site. This dual receptor site antagonism, which occurs with equal potency for both inhibition effects, argues that m18 is not functioning as a mimic of CD4, in spite of the presence of a putative CD4-like loop formed by HCDR3 in the antibody. Consistent with this view, m18 was found to interact with gp120 in the presence of saturating concentrations of a CD4-mimicking small molecule gp120 inhibitor, suggesting that m18 does not require unoccupied CD4 Phe43 binding cavity residues of gp120. Thermodynamic analysis of the m18-gp120 interaction suggests that m18 stabilizes a conformation of gp120 that is unique from and less structured than the CD4-stabilized conformation. Conformational mutants of gp120 were studied for their impact on m18 interaction. Mutations known to disrupt the coreceptor binding region and lead to complete suppression of 17b binding had minimal effects on m18 binding. This argues that energetically important epitopes for m18 binding lie outside the disrupted bridging sheet region used for 17b and coreceptor binding. In contrast, mutations in the CD4 region strongly affected m18 binding. Overall, the results obtained in this work argue that m18, rather than mimicking CD4 directly, suppresses both receptor binding site functions of HIV-1 gp120 by stabilizing a non-productive conformation of the envelope protein. These results can be related to prior findings for the importance of conformational entrapment as a common mode of action for neutralizing CD4bs antibodies, with differences mainly in epitope utilization and extent of gp120 structuring.

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Domestic collaboration
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Web of Science research areas
Biochemistry & Molecular Biology
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