The Preserved HTH-Docking Cleft of HIV-1 Integrase Is Functionally Critical
HIV-1 integrase (IN) catalyzes viral DNA integration into the host genome and facilitates multifunctional steps including virus particle maturation. Competency of IN to form multimeric assemblies is functionally critical, presenting an approach for anti-HIV strategies. Multimerization of IN depends...
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Published in | Structure (London) Vol. 24; no. 11; pp. 1936 - 1946 |
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Main Authors | , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Elsevier Ltd
01.11.2016
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Subjects | |
Online Access | Get full text |
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Summary: | HIV-1 integrase (IN) catalyzes viral DNA integration into the host genome and facilitates multifunctional steps including virus particle maturation. Competency of IN to form multimeric assemblies is functionally critical, presenting an approach for anti-HIV strategies. Multimerization of IN depends on interactions between the distinct subunit domains and among the flanking protomers. Here, we elucidate an overlooked docking cleft of IN core domain that anchors the N-terminal helix-turn-helix (HTH) motif in a highly preserved and functionally critical configuration. Crystallographic structure of IN core domain in complex with Fab specifically targeting this cleft reveals a steric overlap that would inhibit HTH-docking, C-terminal domain contacts, DNA binding, and subsequent multimerization. While Fab inhibits in vitro IN integration activity, in vivo it abolishes virus particle production by specifically associating with preprocessed IN within Gag-Pol and interfering with early cytosolic Gag/Gag-Pol assemblies. The HTH-docking cleft may offer a fresh hotspot for future anti-HIV intervention strategies.
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•Crystal structure of HIV-1 integrase core domain in complex with Fab•The configuration of HTH-motif docking is conserved and functionally imperative•Helix α4 mutually binds viral DNA and crucially mediates integrase multimerization•Intrabody targeting of HTH cleft within Gag-Pol inhibits HIV particle production
HIV-1 integrase protein incorporates the viral DNA into the host genome and facilitates virus particle maturation. Galilee et al. describe a functionally crucial interdomain docking site within integrase. Targeting this site using an intrabody inhibits virus production and may therefore provide a strategy for anti-HIV intervention. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Lead Contact |
ISSN: | 0969-2126 1878-4186 |
DOI: | 10.1016/j.str.2016.08.015 |