ArticleThe Journal of biological chemistry2014
A critical role of the C-terminal segment for allosteric inhibitor-induced aberrant multimerization of HIV-1 integrase.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 30 citations in OpenAlex.
- Targeting Human Immunodeficiency Virus Integrase Beyond the Active Site: The Discovery and Development of Allosteric Integrase Inhibitors.ChemMedChem · 2026Review
- 2-(Trihydroxyphenyl)thienopyrimidinones as Key Scaffolds for Targeting a Novel Allosteric Site of HIV-1 Integrase.Molecules (Basel, Switzerland) · 2025Article
- Article
- Optimizing the Multimerization Properties of Quinoline-Based Allosteric HIV-1 Integrase Inhibitors.Viruses · 2024Review
- The structural and mechanistic bases for the viral resistance to allosteric HIV-1 integrase inhibitor pirmitegravir.bioRxiv : the preprint server for biology · 2024Article
- Dihydroxyphenyl- and Heteroaromatic-Based Thienopyrimidinones to Tackle HIV-1 LEDGF/p75-Dependent IN Activity.Molecules (Basel, Switzerland) · 2023Article
- Structure of a HIV-1 IN-Allosteric inhibitor complex at 2.93 Å resolution: Routes to inhibitor optimization.PLoS pathogens · 2023Article
- Article
- Article
- Structure and function of retroviral integrase.Nature reviews. Microbiology · 2022Review
- Allosteric HIV Integrase Inhibitors Promote Formation of Inactive Branched Polymers via Homomeric Carboxy-Terminal Domain Interactions.Structure (London, England : 1993) · 2021Article
- Exploring the Free-Energy Landscape and Thermodynamics of Protein-Protein Association.Biophysical journal · 2020Article
- A Conformational Escape Reaction of HIV-1 against an Allosteric Integrase Inhibitor.Journal of virology · 2020Article
- HIV-1 integrase tetramers are the antiviral target of pyridine-based allosteric integrase inhibitors.eLife · 2019Article
- Synthesis and Evaluation of Aryl Quinolines as HIV-1 Integrase Multimerization Inhibitors.ACS medicinal chemistry letters · 2018Article
- Structure-function analyses unravel distinct effects of allosteric inhibitors of HIV-1 integrase on viral maturation and integration.The Journal of biological chemistry · 2018Article
- Structural Basis for Inhibitor-Induced Aggregation of HIV Integrase.PLoS biology · 2016Article
- Allosteric HIV-1 integrase inhibitors promote aberrant protein multimerization by directly mediating inter-subunit interactions: Structural and thermodynamic modeling studies.Protein science : a publication of the Protein Society · 2016Article
- The Preserved HTH-Docking Cleft of HIV-1 Integrase Is Functionally Critical.Structure (London, England : 1993) · 2016Article
- Retroviral DNA Integration.Chemical reviews · 2016Review
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
Allosteric HIV-1 integrase (IN) inhibitors (ALLINIs) are a promising class of antiretroviral agents for clinical development. Although ALLINIs promote aberrant IN multimerization and inhibit IN interaction with its cellular cofactor LEDGF/p75 with comparable potencies in vitro, their primary mechanism of action in infected cells is through inducing aberrant multimerization of IN. Crystal structures have shown that ALLINIs bind at the IN catalytic core domain dimer interface and bridge two interacting subunits. However, how these interactions promote higher-order protein multimerization is not clear. Here, we used mass spectrometry-based protein footprinting to monitor surface topology changes in full-length WT and the drug-resistant A128T mutant INs in the presence of ALLINI-2. These experiments have identified protein-protein interactions that extend beyond the direct inhibitor binding site and which lead to aberrant multimerization of WT but not A128T IN. Specifically, we demonstrate that C-terminal residues Lys-264 and Lys-266 play an important role in the inhibitor induced aberrant multimerization of the WT protein. Our findings provide structural clues for exploiting IN multimerization as a new, attractive therapeutic target and are expected to facilitate development of improved inhibitors.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.