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Crystal structure of HIV-1 primary receptor CD4 in complex with a potent antiviral antibody.

Abstract
Ibalizumab is a humanized, anti-CD4 monoclonal antibody. It potently blocks HIV-1 infection and targets an epitope in the second domain of CD4 without interfering with immune functions mediated by interaction of CD4 with major histocompatibility complex (MHC) class II molecules. We report here the crystal structure of ibalizumab Fab fragment in complex with the first two domains (D1-D2) of CD4 at 2.2 Å resolution. Ibalizumab grips CD4 primarily by the BC-loop (residues 121-125) of D2, sitting on the opposite side of gp120 and MHC-II binding sites. No major conformational change in CD4 accompanies binding to ibalizumab. Both monovalent and bivalent forms of ibalizumab effectively block viral infection, suggesting that it does not need to crosslink CD4 to exert antiviral activity. While gp120-induced structural rearrangements in CD4 are probably minimal, CD4 structural rigidity is dispensable for ibalizumab inhibition. These results could guide CD4-based immunogen design and lead to a better understanding of HIV-1 entry.
AuthorsMichael M Freeman, Michael S Seaman, Sophia Rits-Volloch, Xinguo Hong, Chia-Ying Kao, David D Ho, Bing Chen
JournalStructure (London, England : 1993) (Structure) Vol. 18 Issue 12 Pg. 1632-41 (Dec 08 2010) ISSN: 1878-4186 [Electronic] United States
PMID21134642 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
CopyrightCopyright © 2010 Elsevier Ltd. All rights reserved.
Chemical References
  • Antibodies, Monoclonal
  • Antibodies, Viral
  • Antigen-Antibody Complex
  • Antiviral Agents
  • CD4 Antigens
  • HIV Envelope Protein gp120
  • Receptors, Virus
  • ibalizumab
Topics
  • Animals
  • Antibodies, Monoclonal (chemistry, metabolism)
  • Antibodies, Viral (chemistry, metabolism)
  • Antigen-Antibody Complex (chemistry)
  • Antiviral Agents (chemistry, metabolism)
  • CD4 Antigens (chemistry, immunology, metabolism)
  • Crystallography, X-Ray
  • HIV Envelope Protein gp120 (chemistry, immunology, metabolism)
  • HIV-1 (metabolism)
  • Humans
  • Mice
  • Models, Biological
  • Models, Molecular
  • Protein Structure, Quaternary
  • Protein Structure, Secondary
  • Receptors, Virus (chemistry, immunology, metabolism)

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