4Q6I

Crystal structure of murine 2D5 Fab, a potent anti-CD4 HIV-1-neutralizing antibody in complex with CD4

Summary for 4Q6I

• Entry DOI: 10.2210/pdb4q6i/pdb
• Descriptor: Light chain of murine 2D5 Fab, Heavy chain of murine 2D5 Fab, T-cell surface glycoprotein CD4 (3 entities in total)
• Functional Keywords: ig fold, antibody, anti-cd4, hiv-1 neutralization, cd4, immune system
• Biological source: Homo sapiens (human); More
• Cellular location: Cell membrane; Single-pass type I membrane protein: P01730
• Total number of polymer chains: 12
• Total formula weight: 287960.09

Authors

Boyington, J.C.,Nabel, G.J.,Mascola, J.R. (deposition date: 2014-04-22, release date: 2014-07-23, Last modification date: 2024-11-06)

Primary citation

Pegu, A.,Yang, Z.Y.,Boyington, J.C.,Wu, L.,Ko, S.Y.,Schmidt, S.D.,McKee, K.,Kong, W.P.,Shi, W.,Chen, X.,Todd, J.P.,Letvin, N.L.,Huang, J.,Nason, M.C.,Hoxie, J.A.,Kwong, P.D.,Connors, M.,Rao, S.S.,Mascola, J.R.,Nabel, G.J.
Neutralizing antibodies to HIV-1 envelope protect more effectively in vivo than those to the CD4 receptor.
Sci Transl Med, 6:243ra88-243ra88, 2014

PubMed Abstract: HIV-1 infection depends on effective viral entry mediated by the interaction of its envelope (Env) glycoprotein with specific cell surface receptors. Protective antiviral antibodies generated by passive or active immunization must prevent these interactions. Because the HIV-1 Env is highly variable, attention has also focused on blocking the HIV-1 primary cell receptor CD4. We therefore analyzed the in vivo protective efficacy of three potent neutralizing monoclonal antibodies (mAbs) to HIV-1 Env compared to an antibody against the CD4 receptor. Protection was assessed after mucosal challenge of rhesus macaques with simian/HIV (SHIV). Despite its comparable or greater neutralization potency in vitro, the anti-CD4 antibody did not provide effective protection in vivo, whereas the HIV-1-specific mAbs VRC01, 10E8, and PG9, targeting the CD4 binding site, membrane-proximal, and V1V2 glycan Env regions, respectively, conferred complete protection, albeit at different relative potencies. These findings demonstrate the protective efficacy of broadly neutralizing antibodies directed to the HIV-1 Env and suggest that targeting the HIV-1 Env is preferable to the cell surface receptor CD4 for the prevention of HIV-1 transmission.

PubMed: 24990883
DOI: 10.1126/scitranslmed.3008992

Experimental method

X-RAY DIFFRACTION (3.65 Å)