The Preserved HTH-Docking Cleft of HIV-1 Integrase Is Functionally Critical.

TitleThe Preserved HTH-Docking Cleft of HIV-1 Integrase Is Functionally Critical.
Publication TypeJournal Article
Year of Publication2016
AuthorsGalilee, Meytal, Britan-Rosich Elena, Griner Sarah L., Uysal Serdar, Baumgärtel Viola, Lamb Don C., Kossiakoff Anthony A., Kotler Moshe, Stroud Robert M., Marx Ailie, and Alian Akram
Date Published2016 Nov 01
KeywordsCatalytic Domain, Crystallography, X-Ray, Helix-Turn-Helix Motifs, HIV Integrase, HIV-1, Models, Molecular, Molecular Docking Simulation, Protein Binding, Protein Multimerization, Protein Structure, Secondary, RNA, Viral

<p>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.</p>

Alternate JournalStructure
PubMed ID27692964
PubMed Central IDPMC5093063
Grant ListP50 GM082250 / GM / NIGMS NIH HHS / United States
R01 GM117372 / GM / NIGMS NIH HHS / United States
U01 GM094588 / GM / NIGMS NIH HHS / United States

University of Toronto  UCSF  The University of Chicago  QB3  Chicago Biomedical Consortium