ArticleBMC chemical biology2012
HIV-1 Nef interaction influences the ATP-binding site of the Src-family kinase, Hck.
Article in BMC chemical biology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 22 citations in OpenAlex.
- Novel HCK-associated mutation causing autoinflammatory disorder with pulmonary manifestations in a pediatric patient.Pediatric rheumatology online journal · 2025Article
- Constitutive activation of the Src-family kinases Fgr and Hck enhances the tumor burden of acute myeloid leukemia cells in immunocompromised mice.Scientific reports · 2025Article
- Direct interaction between ABCA1 and HIV-1 Nef: Molecular modeling and virtual screening for inhibitors.Computational and structural biotechnology journal · 2021Article
- Structure, function, and inhibitor targeting of HIV-1 Nef-effector kinase complexes.The Journal of biological chemistry · 2020Review
- Inhibition of Hematopoietic Cell Kinase Activity Suppresses Myeloid Cell-Mediated Colon Cancer Progression.Cancer cell · 2017Article
- Hydrogen Exchange Mass Spectrometry of Related Proteins with Divergent Sequences: A Comparative Study of HIV-1 Nef Allelic Variants.Journal of the American Society for Mass Spectrometry · 2016Article
- Subtle Dynamic Changes Accompany Hck Activation by HIV-1 Nef and are Reversed by an Antiretroviral Kinase Inhibitor.Biochemistry · 2015Article
- Hematopoietic cell kinase (HCK) as a therapeutic target in immune and cancer cells.Oncotarget · 2015Review
- Applications of hydrogen/deuterium exchange MS from 2012 to 2014.Analytical chemistry · 2015Review
- Interaction with the Src homology (SH3-SH2) region of the Src-family kinase Hck structures the HIV-1 Nef dimer for kinase activation and effector recruitment.The Journal of biological chemistry · 2014Article
- Small molecule inhibitors of the HIV-1 virulence factor, Nef.Drug discovery today. Technologies · 2013Review
- HIV-1 infection of T cells and macrophages are differentially modulated by virion-associated Hck: a Nef-dependent phenomenon.Viruses · 2013Article
- Viral proteins and Src family kinases: Mechanisms of pathogenicity from a "liaison dangereuse".World journal of virology · 2013Review
- Nef alleles from all major HIV-1 clades activate Src-family kinases and enhance HIV-1 replication in an inhibitor-sensitive manner.PloS one · 2012Article
Corrections and comments
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
Abstract
backgroundNef is an HIV-1 accessory protein essential for viral replication and AIDS progression. Nef interacts with a multitude of host cell signaling partners, including members of the Src kinase family. Nef preferentially activates Hck, a Src-family kinase (SFK) strongly expressed in macrophages and other HIV target cells, by binding to its regulatory SH3 domain. Recently, we identified a series of kinase inhibitors that preferentially inhibit Hck in the presence of Nef. These compounds also block Nef-dependent HIV replication, validating the Nef-SFK signaling pathway as an antiretroviral drug target. Our findings also suggested that by binding to the Hck SH3 domain, Nef indirectly affects the conformation of the kinase active site to favor inhibitor association.
resultsTo test this hypothesis, we engineered a "gatekeeper" mutant of Hck with enhanced sensitivity to the pyrazolopyrimidine tyrosine kinase inhibitor, NaPP1. We also modified the RT loop of the Hck SH3 domain to enhance interaction of the kinase with Nef. This modification stabilized Nef:Hck interaction in solution-based kinase assays, as a way to mimic the more stable association that likely occurs at cellular membranes. Introduction of the modified RT loop rendered Hck remarkably more sensitive to activation by Nef, and led to a significant decrease in the Km for ATP as well as enhanced inhibitor potency.
conclusionsThese observations suggest that stable interaction with Nef may induce Src-family kinase active site conformations amenable to selective inhibitor targeting.
Identifiers
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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.