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Journal of Virology, September 2009, p. 8451-8462, Vol. 83, No. 17
0022-538X/09/$08.00+0     doi:10.1128/JVI.00685-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

A Conformational Switch in Human Immunodeficiency Virus gp41 Revealed by the Structures of Overlapping Epitopes Recognized by Neutralizing Antibodies {triangledown}

Robert Pejchal,1 Johannes S. Gach,2 Florence M. Brunel,3 Rosa M. Cardoso,1 Robyn L. Stanfield,1 Philip E. Dawson,3,4 Dennis R. Burton,1,2 Michael B. Zwick,2* and Ian A. Wilson1,4*

Department of Molecular Biology,1 Department of Immunology and Microbial Science,2 Department of Chemistry and Cell Biology,3 Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California 920374

Received 2 April 2009/ Accepted 4 June 2009

The membrane-proximal external region (MPER) of the human immunodeficiency virus (HIV) envelope glycoprotein (gp41) is critical for viral fusion and infectivity and is the target of three of the five known broadly neutralizing HIV type 1 (HIV-1) antibodies, 2F5, Z13, and 4E10. Here, we report the crystal structure of the Fab fragment of Z13e1, an affinity-enhanced variant of monoclonal antibody Z13, in complex with a 12-residue peptide corresponding to the core epitope (W670NWFDITN677) at 1.8-Å resolution. The bound peptide adopts an S-shaped conformation composed of two tandem, perpendicular helical turns. This conformation differs strikingly from the {alpha}-helical structure adopted by an overlapping MPER peptide bound to 4E10. Z13e1 binds to an elbow in the MPER at the membrane interface, making relatively few interactions with conserved aromatics (Trp672 and Phe673) that are critical for 4E10 recognition. The comparison of the Z13e1 and 4E10 epitope structures reveals a conformational switch such that neutralization can occur by the recognition of the different conformations and faces of the largely amphipathic MPER. The Z13e1 structure provides significant new insights into the dynamic nature of the MPER, which likely is critical for membrane fusion, and it has significant implications for mechanisms of HIV-1 neutralization by MPER antibodies and for the design of HIV-1 immunogens.

* Corresponding author. Mailing address for I. A. Wilson: Department of Molecular Biology, BCC206, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037. Phone: (858) 784-9706. Fax: (858) 794-2980. E-mail: wilson{at}scripps.edu. Mailing address for M. B. Zwick: Department of Immunology and Microbial Science, IMM2, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037. Phone: (858) 784-2833. Fax: (858) 784-8360. E-mail: zwick{at}scripps.edu

{triangledown} Published ahead of print on 10 June 2009.

Journal of Virology, September 2009, p. 8451-8462, Vol. 83, No. 17
0022-538X/09/$08.00+0     doi:10.1128/JVI.00685-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Bryson, S., Julien, J.-P., Hynes, R. C., Pai, E. F. (2009). Crystallographic Definition of the Epitope Promiscuity of the Broadly Neutralizing Anti-Human Immunodeficiency Virus Type 1 Antibody 2F5: Vaccine Design Implications. J. Virol. 83: 11862-11875 [Abstract] [Full Text]  
  • Gray, E. S., Madiga, M. C., Moore, P. L., Mlisana, K., Abdool Karim, S. S., Binley, J. M., Shaw, G. M., Mascola, J. R., Morris, L. (2009). Broad Neutralization of Human Immunodeficiency Virus Type 1 Mediated by Plasma Antibodies against the gp41 Membrane Proximal External Region. J. Virol. 83: 11265-11274 [Abstract] [Full Text]  


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