Characterization of HIV-1 integrase interaction with human Ku70 protein and initial implications for drug targeting

Abstract Human Ku70/Ku80 protein is known to influence HIV-1 replication. One of the possible reasons may be the protection of integrase from proteasomal degradation by Ku70 subunit. We demonstrated that recombinant HIV-1 integrase and Ku70 form a stable complex, while no interaction of Ku70 with in...

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Autores principales:	Andrey N. Anisenko, Ekaterina S. Knyazhanskaya, Artur O. Zalevsky, Julia Yu Agapkina, Aleksander I. Sizov, Timofey S. Zatsepin, Marina B. Gottikh
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/c745e5f6f43046aebb85df84c70d8236
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spelling	oai:doaj.org-article:c745e5f6f43046aebb85df84c70d82362021-12-02T16:08:21ZCharacterization of HIV-1 integrase interaction with human Ku70 protein and initial implications for drug targeting10.1038/s41598-017-05659-52045-2322https://doaj.org/article/c745e5f6f43046aebb85df84c70d82362017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-05659-5https://doaj.org/toc/2045-2322Abstract Human Ku70/Ku80 protein is known to influence HIV-1 replication. One of the possible reasons may be the protection of integrase from proteasomal degradation by Ku70 subunit. We demonstrated that recombinant HIV-1 integrase and Ku70 form a stable complex, while no interaction of Ku70 with integrase from prototype foamy virus was observed. By analyzing protein subdomains we determined two binding sites in the structure of both Ku70 and integrase: the 51–160 a.a. region of integrase interacts with residues 251–438 of Ku70, whereas Ku70 N-terminal domain (1–250 a.a.) contacts an α6-helix in the 200–220 a.a. integrase region. Single substitutions within integrase (E212A or L213A) block the interaction with Ku70 thus indicating that the binding site formed by the 200–220 a.a. integrase region is crucial for complex formation. E212A/L213A substitutions decreased the integrase capacity to bind Ku70 in HEK293T cells. A conjugate of 2′-ОMe-GGUUUUUGUGU oligonucleotide with eosin is shown by molecular modeling to shield integrase residues E212/L213 and is effective in blocking complex formation of Ku70 with integrase what makes the complex between α6-helix and Ku70(1–250) a possible target for drug development.Andrey N. AnisenkoEkaterina S. KnyazhanskayaArtur O. ZalevskyJulia Yu AgapkinaAleksander I. SizovTimofey S. ZatsepinMarina B. GottikhNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-14 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Andrey N. Anisenko Ekaterina S. Knyazhanskaya Artur O. Zalevsky Julia Yu Agapkina Aleksander I. Sizov Timofey S. Zatsepin Marina B. Gottikh Characterization of HIV-1 integrase interaction with human Ku70 protein and initial implications for drug targeting
description	Abstract Human Ku70/Ku80 protein is known to influence HIV-1 replication. One of the possible reasons may be the protection of integrase from proteasomal degradation by Ku70 subunit. We demonstrated that recombinant HIV-1 integrase and Ku70 form a stable complex, while no interaction of Ku70 with integrase from prototype foamy virus was observed. By analyzing protein subdomains we determined two binding sites in the structure of both Ku70 and integrase: the 51–160 a.a. region of integrase interacts with residues 251–438 of Ku70, whereas Ku70 N-terminal domain (1–250 a.a.) contacts an α6-helix in the 200–220 a.a. integrase region. Single substitutions within integrase (E212A or L213A) block the interaction with Ku70 thus indicating that the binding site formed by the 200–220 a.a. integrase region is crucial for complex formation. E212A/L213A substitutions decreased the integrase capacity to bind Ku70 in HEK293T cells. A conjugate of 2′-ОMe-GGUUUUUGUGU oligonucleotide with eosin is shown by molecular modeling to shield integrase residues E212/L213 and is effective in blocking complex formation of Ku70 with integrase what makes the complex between α6-helix and Ku70(1–250) a possible target for drug development.
format	article
author	Andrey N. Anisenko Ekaterina S. Knyazhanskaya Artur O. Zalevsky Julia Yu Agapkina Aleksander I. Sizov Timofey S. Zatsepin Marina B. Gottikh
author_facet	Andrey N. Anisenko Ekaterina S. Knyazhanskaya Artur O. Zalevsky Julia Yu Agapkina Aleksander I. Sizov Timofey S. Zatsepin Marina B. Gottikh
author_sort	Andrey N. Anisenko
title	Characterization of HIV-1 integrase interaction with human Ku70 protein and initial implications for drug targeting
title_short	Characterization of HIV-1 integrase interaction with human Ku70 protein and initial implications for drug targeting
title_full	Characterization of HIV-1 integrase interaction with human Ku70 protein and initial implications for drug targeting
title_fullStr	Characterization of HIV-1 integrase interaction with human Ku70 protein and initial implications for drug targeting
title_full_unstemmed	Characterization of HIV-1 integrase interaction with human Ku70 protein and initial implications for drug targeting
title_sort	characterization of hiv-1 integrase interaction with human ku70 protein and initial implications for drug targeting
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/c745e5f6f43046aebb85df84c70d8236
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Characterization of HIV-1 integrase interaction with human Ku70 protein and initial implications for drug targeting

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