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RESEARCH Open Access Structural basis for the inhibition of HIV-1 Nef by a high-affinity binding single-domain antibody
BibTeX
@MISC{Lülf_researchopen,
author = {Sebastian Lülf and Julie Matz and Marie-christine Rouyez and Annika Järviluoma and Kalle Saksela and Serge Benichou and Matthias Geyer},
title = {RESEARCH Open Access Structural basis for the inhibition of HIV-1 Nef by a high-affinity binding single-domain antibody},
year = {}
}
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Abstract
Background: The HIV-1 Nef protein is essential for AIDS pathogenesis by its interaction with host cell surface receptors and signaling factors. Despite its critical role as a virulence factor Nef is not targeted by current antiviral strategies. Results: We have determined the crystal structure of the complex formed by a camelid single-domain antibody fragment, termed sdAb19, bound to HIV-1 Nef together with a stabilizing SH3 domain. sdAb19 forms a stoichiometric 1:1 complex with Nef and binds to a conformationally conserved surface at the C-terminus of Nef that overlaps with functionally important interaction sites involved in Nef-induced perturbations of signaling and trafficking pathways. The antibody fragment binds Nef with low nanomolar affinity, which could be attenuated to micromolar affinity range by site-directed mutagenesis of key interaction residues in sdAb19. Fusion of the SH3 domain to sdAb19, termed Neffin, leads to a significantly increased affinity for Nef and formation of a stoichiometric 2:2 Nef–Neffin complex. The 19 kDa Neffin protein inhibits all functions of Nef as CD4 and MHC-I downregulation, association with Pak2, and the increase in virus infectivity and replication. Conclusions: Together, sdAb19 and Neffin thus represent efficient tools for the rational development of antiviral strategies against HIV-1 Nef.
Keyphrases
hiv-1 nef research open access structural basis high-affinity binding single-domain antibody sh3 domain rational development important interaction site efficient tool key interaction residue host cell surface receptor antiviral strategy kda neffin protein current antiviral strategy site-directed mutagenesis low nanomolar affinity virus infectivity affinity range nef-induced perturbation crystal structure camelid single-domain antibody fragment critical role mhc-i downregulation nef neffin complex virulence factor nef hiv-1 nef protein aid pathogenesis antibody fragment bind nef
