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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 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 ?6-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'-?Me-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 ?6-helix and Ku70(1-250) a possible target for drug development.

SUBMITTER: Anisenko AN 

PROVIDER: S-EPMC5514147 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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

Anisenko Andrey N AN   Knyazhanskaya Ekaterina S ES   Zalevsky Artur O AO   Agapkina Julia Yu JY   Sizov Aleksander I AI   Zatsepin Timofey S TS   Gottikh Marina B MB  

Scientific reports 20170717 1


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  ...[more]

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