Molecular design, functional characterization and structural basis of a protein inhibitor against the HIV-1 pathogenicity factor Nef.

Increased spread of HIV-1 and rapid emergence of drug resistance warrants development of novel antiviral strategies. Nef, a critical viral pathogenicity factor that interacts with host cell factors but lacks enzymatic activity, is not targeted by current antiviral measures. Here we inhibit Nef funct...

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Autores principales:	Sebastian Breuer, Simone I Schievink, Antje Schulte, Wulf Blankenfeldt, Oliver T Fackler, Matthias Geyer
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/ed2bf57ea86a4cf89576571d0113c113
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spelling	oai:doaj.org-article:ed2bf57ea86a4cf89576571d0113c1132021-11-18T06:53:32ZMolecular design, functional characterization and structural basis of a protein inhibitor against the HIV-1 pathogenicity factor Nef.1932-620310.1371/journal.pone.0020033https://doaj.org/article/ed2bf57ea86a4cf89576571d0113c1132011-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21625496/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Increased spread of HIV-1 and rapid emergence of drug resistance warrants development of novel antiviral strategies. Nef, a critical viral pathogenicity factor that interacts with host cell factors but lacks enzymatic activity, is not targeted by current antiviral measures. Here we inhibit Nef function by simultaneously blocking several highly conserved protein interaction surfaces. This strategy, referred to as "wrapping Nef", is based on structure-function analyses that led to the identification of four target sites: (i) SH3 domain interaction, (ii) interference with protein transport processes, (iii) CD4 binding and (iv) targeting to lipid membranes. Screening combinations of Nef-interacting domains, we developed a series of small Nef interacting proteins (NIs) composed of an SH3 domain optimized for binding to Nef, fused to a sequence motif of the CD4 cytoplasmic tail and combined with a prenylation signal for membrane association. NIs bind to Nef in the low nM affinity range, associate with Nef in human cells and specifically interfere with key biological activities of Nef. Structure determination of the Nef-inhibitor complex reveals the molecular basis for binding specificity. These results establish Nef-NI interfaces as promising leads for the development of potent Nef inhibitors.Sebastian BreuerSimone I SchievinkAntje SchulteWulf BlankenfeldtOliver T FacklerMatthias GeyerPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 5, p e20033 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Sebastian Breuer Simone I Schievink Antje Schulte Wulf Blankenfeldt Oliver T Fackler Matthias Geyer Molecular design, functional characterization and structural basis of a protein inhibitor against the HIV-1 pathogenicity factor Nef.
description	Increased spread of HIV-1 and rapid emergence of drug resistance warrants development of novel antiviral strategies. Nef, a critical viral pathogenicity factor that interacts with host cell factors but lacks enzymatic activity, is not targeted by current antiviral measures. Here we inhibit Nef function by simultaneously blocking several highly conserved protein interaction surfaces. This strategy, referred to as "wrapping Nef", is based on structure-function analyses that led to the identification of four target sites: (i) SH3 domain interaction, (ii) interference with protein transport processes, (iii) CD4 binding and (iv) targeting to lipid membranes. Screening combinations of Nef-interacting domains, we developed a series of small Nef interacting proteins (NIs) composed of an SH3 domain optimized for binding to Nef, fused to a sequence motif of the CD4 cytoplasmic tail and combined with a prenylation signal for membrane association. NIs bind to Nef in the low nM affinity range, associate with Nef in human cells and specifically interfere with key biological activities of Nef. Structure determination of the Nef-inhibitor complex reveals the molecular basis for binding specificity. These results establish Nef-NI interfaces as promising leads for the development of potent Nef inhibitors.
format	article
author	Sebastian Breuer Simone I Schievink Antje Schulte Wulf Blankenfeldt Oliver T Fackler Matthias Geyer
author_facet	Sebastian Breuer Simone I Schievink Antje Schulte Wulf Blankenfeldt Oliver T Fackler Matthias Geyer
author_sort	Sebastian Breuer
title	Molecular design, functional characterization and structural basis of a protein inhibitor against the HIV-1 pathogenicity factor Nef.
title_short	Molecular design, functional characterization and structural basis of a protein inhibitor against the HIV-1 pathogenicity factor Nef.
title_full	Molecular design, functional characterization and structural basis of a protein inhibitor against the HIV-1 pathogenicity factor Nef.
title_fullStr	Molecular design, functional characterization and structural basis of a protein inhibitor against the HIV-1 pathogenicity factor Nef.
title_full_unstemmed	Molecular design, functional characterization and structural basis of a protein inhibitor against the HIV-1 pathogenicity factor Nef.
title_sort	molecular design, functional characterization and structural basis of a protein inhibitor against the hiv-1 pathogenicity factor nef.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/ed2bf57ea86a4cf89576571d0113c113
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Molecular design, functional characterization and structural basis of a protein inhibitor against the HIV-1 pathogenicity factor Nef.

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