Monoclonal Antibody m18 Paratope Leading to Dual Receptor Antagonism of HIV-1 gp120
| Autor: | Srivats Rajagopal, Dimiter S. Dimitrov, Syna Kuriakose Gift, Karyn McFadden, Isaac Zentner, Irwin Chaiken, Mei-Yun Zhang |
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| Rok vydání: | 2011 |
| Předmět: |
Models
Molecular Protein Conformation medicine.drug_class Mutant Complementarity determining region HIV Antibodies HIV Envelope Protein gp120 Biology Monoclonal antibody Binding Competitive Biochemistry Article Epitopes Immunoglobulin Fab Fragments medicine Humans Surface plasmon resonance Neutralizing antibody Receptor Binding Sites Antibodies Monoclonal Antibodies Neutralizing Complementarity Determining Regions Molecular biology Cell biology CD4 Antigens Mutation HIV-1 biology.protein Paratope Antibody Protein Binding |
| Zdroj: | Biochemistry. 50:2769-2779 |
| ISSN: | 1520-4995 0006-2960 |
| Popis: | We sought to identify sequences in the monoclonal antibody m18 complementarity determining regions (CDRs) that are responsible for its interaction with HIV-1 gp120 and inhibition of the envelope receptor binding sites. In the accompanying paper (DOI 10.1021/bi101160r), we reported that m18 inhibits CD4 binding through a nonactivating mechanism that, at the same time, induces conformational effects leading to inhibition of the coreceptor site. Here, we sought to define the structural elements in m18 responsible for these actions. Direct binding and competition analyses using surface plasmon resonance showed that YU-2 gp120 binding is stabilized by a broad paratope of residues in the m18 CDRs. Additionally, several m18 residues were identified for which mutants retained high affinity for gp120 but had suppressed CD4 and 17b inhibition activities. A subset of these mutants did, however, neutralize HXBc2 viral infection. The results obtained in this work demonstrate that the combined m18 paratope contains subsets of residues that are differentially important for the binding and inhibition functions of the m18 neutralizing antibody. The data also add to prior observations that high-affinity antibodies that do not inhibit monomeric gp120 receptor site interactions may still exhibit significant antiviral activity. |
| Databáze: | OpenAIRE |
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