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Structure. 2016 Nov 1;24(11):1936-1946. doi: 10.1016/j.str.2016.08.015. Epub 2016 Sep 29.

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

Author information

1
Department of Biology, Technion - Israel Institute of Technology, Haifa 320003, Israel.
2
Department of Immunology and Pathology, The Lautenberg Center for General and Tumor Immunology, The Hebrew University Hadassah Medical School, Jerusalem 91120, Israel.
3
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA.
4
Department of Biophysics, Bezmialem Vakif University, Istanbul 34093, Turkey.
5
Physical Chemistry, Department of Chemistry, Nanosystem Initiative Munich (NIM), Center for Integrated Protein Science Munich (CiPSM), Center for NanoScience (CeNS), Ludwig-Maximilians-Universität München, Munich 81377, Germany.
6
Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL 60637, USA.
7
Department of Biology, Technion - Israel Institute of Technology, Haifa 320003, Israel. Electronic address: alian@tx.technion.ac.il.

Abstract

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.

PMID:
27692964
PMCID:
PMC5093063
DOI:
10.1016/j.str.2016.08.015
[Indexed for MEDLINE]
Free PMC Article

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