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Highly conserved β16/β17 β-hairpin structure in human immunodeficiency virus type 1 YU2 gp120 is critical for CCR5 binding

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Abstract

Whereas gp120 CD4-induced structures have been largely documented and at least in part elucidated by crystallization, information about gp120 coreceptor-induced structures remains incomplete despite numerous studies. In this work, mutations were carried out in a selected internal region of HIV-1/YU2 gp120, proximal to the CD4-binding site, because of its highly conserved nature among retroviruses and its high structural stability. The targeted residues, belonging to the β16/β17 β-hairpin, modulate gp120 binding to CD4 and gp120-CD4 complex binding to CCR5. Thus, it appears that this gp120 structure acts as a hinge between the CD4-binding site and the putative coreceptor binding structure. Substitution of amino acid residues like E381A did not affect gp120 binding to CD4 and did not induce significant structural changes in gp120, as demonstrated by epitope analysis, BIACORE analysis, and circular dichroism. Nevertheless, E381 has a critical influence on the maintenance of CCR5 coreceptor binding by forming a salt bridge with K207. Another important element of the β-hairpin in this interaction is the probable hydrophobic link between F383 and I420. Altogether, these results suggest that the β-hairpin structure likely governs interactions between the surface of gp120 with native CCR5 or the CCR5 amino-terminal domain (CCR5-Nt). The mutations within the β-hairpin had a direct effect on the proximal surface of the bridging sheet, the putative CCR5 surface, and the gp120 YU2 HIV-1–CD4 binding site. These results on the gp120-CCR5-Nt binding mechanism contribute to our understanding of CCR5 and HIV-1 gp120 association and HIV-1 entry; they may also contribute to designing novel inhibitors.

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Acknowledgements

We are indebted to Sharon Lynn Salhi for editing the manuscript, Vincent Simon, Philippe Barthe, Loïc Martin, Claudio Vita and Joseph Sodroski for their skillful help, and the late Dominique Dormont for his support. This work was supported by the Agence Nationale de Recherches sur le SIDA (ANRS, France) and by NIH grant AI24030.

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Authors and Affiliations

  1. Laboratoire d’Immunologie Rétrovirale et Moléculaire, Institut Français de Recherches pour le Développement (IRD), UR 034, 240 Av. Emile Jeanbrau, Etablissement Français du Sang, 34094, Montpellier, France

    Alain Mechulam, Dorothée Missé, Johanna Gajardo & Francisco Veas

  2. Groupe Baculovirus et Thérapie, CNRS GDR 2590, 30380, Saint-Christol-lez-Alès, France

    Martine Cerutti

  3. Centre de Pharmacologie et Biotechnologie pour la Santé, Faculté de Pharmacie, CNRS UMR 516, 34093, Montpellier, France

    Martine Pugnière & Françoise Roquet

  4. Department of Pediatrics, Tulane University Medical Center, New Orleans, LA, 70012, USA

    James Robinson

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  1. Alain Mechulam
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  2. Martine Cerutti
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Correspondence to Francisco Veas.

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M. Cerutti and M. Pugnière contributed equally to this work.

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Mechulam, A., Cerutti, M., Pugnière, M. et al. Highly conserved β16/β17 β-hairpin structure in human immunodeficiency virus type 1 YU2 gp120 is critical for CCR5 binding. J Mol Med 83, 542–552 (2005). https://doi.org/10.1007/s00109-005-0673-1

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