The crystal structure of HIV-1 Nef protein bound to the Fyn kinase SH3 domain suggests a role for this complex in altered T cell receptor signaling

Arold, Stefan T.; Franken, P.; Strub, Marie‐Paule; Hoh, François; Bénichou, Serge; Bénarous, Richard; Dumas, Christian

doi:10.1016/s0969-2126(97)00286-4

Cited by 201 publications

(247 citation statements)

References 72 publications

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“…5] and allowed, after clustering, to keep 33 candidates. Ten of these molecules (henceforth referred to as D1 to D10 for Diversity compounds [1][2][3][4][5][6][7][8][9][10] were selected by chemical and geometrical properties for experimental evaluation.…”

Section: Resultsmentioning

confidence: 99%

“…Indeed, in this model, the D1 hydrophobic phenyl derivative superimposed the SH3 Ile-96 hydrophobic side chain, which was identified as a ''hot spot'' in a structure-activity relationship program (14). On the other side of the molecule, a benzoic acid derivative can engage in an electrostatic interaction with the protein, replacing the carboxyl group of the Asp-99 SH3 residue (10).…”

Section: Resultsmentioning

confidence: 99%

“…The crystal structure of the unliganded core domain of Nef, as well as of Nef complexed to the SH3 domain, provides an essential template for the design of potential inhibitors of Nef's action (10,11) (Fig. 1a).…”

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confidence: 99%

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Protein–protein interaction inhibition (2P2I) combining high throughput and virtual screening: Application to the HIV-1 Nef protein

Betzi

Restouin

Opi

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

109

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Protein-protein recognition is the cornerstone of multiple cellular and pathological functions. Therefore, protein-protein interaction inhibition (2P2I) is endowed with great therapeutic potential despite the initial belief that 2P2I was refractory to small-molecule intervention. Improved knowledge of complex molecular binding surfaces has recently stimulated renewed interest for 2P2I, especially after identification of ''hot spots'' and first inhibitory compounds. However, the combination of target complexity and lack of starting compound has thwarted experimental results and created intellectual barriers. Here we combined virtual and experimental screening when no previously known inhibitors can be used as starting point in a structure-based research program that targets an SH3 binding surface of the HIV type I Nef protein. High-throughput docking and application of a pharmacophoric filter on one hand and search for analogy on the other hand identified drug-like compounds that were further confirmed to bind Nef in the micromolar range (isothermal titration calorimetry), to target the Nef SH3 binding surface (NMR experiments), and to efficiently compete for Nef-SH3 interactions (cell-based assay, GST pull-down). Initial identification of these compounds by virtual screening was validated by screening of the very same library of compounds in the cell-based assay, demonstrating that a significant enrichment factor was attained by the in silico screening. To our knowledge, our results identify the first set of drug-like compounds that functionally target the HIV-1 Nef SH3 binding surface and provide the basis for a powerful discovery process that should help to speed up 2P2I strategies and open avenues for new class of antiviral molecules.drug design ͉ Src homology 3 ͉ docking ͉ scoring function ͉ NMR

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Protein–protein interaction inhibition (2P2I) combining high throughput and virtual screening: Application to the HIV-1 Nef protein

Betzi

Restouin

Opi

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

109

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“…The interaction depends on a well conserved surface-exposed hydrophobic patch, reported to form an interface between Nef molecules in crystals of the Nef core domain (45). However, myristylated Nef is predominantly monomeric in solution (46,47), and the binding site for Dyn2 would thus be expected to be accessible on native Nef.…”

Section: Discussionmentioning

confidence: 99%

Dynamin 2 is required for the enhancement of HIV-1 infectivity by Nef

Pizzato

Helander

Попова

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

110

150

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Nef is a virulence factor of HIV-1 and other primate lentiviruses that is crucial for rapid progression to AIDS. In cell culture, Nef increases the infectivity of HIV-1 progeny virions by an unknown mechanism. We now show that dynamin 2 (Dyn2), a key regulator of vesicular trafficking, is a binding partner of Nef that is required for its ability to increase viral infectivity. Dominant-negative Dyn2 or the depletion of Dyn2 by small interfering RNA potently inhibited the effect of Nef on HIV-1 infectivity. Furthermore, in Dyn2-depleted cells, this function of Nef could be rescued by ectopically expressed Dyn2 but not by Dyn1, a closely related isoform that does not bind Nef. The infectivity enhancement by Nef also depended on clathrin, because it was diminished in clathrin-depleted cells and profoundly inhibited in cells expressing the clathrin-binding domain of AP180, which blocks clathrin-coated pit formation but not clathrin-independent endocytosis. Together, these findings imply that the infectivity enhancement activity of Nef depends on Dyn2-and clathrin-mediated membrane invagination events.HIV accessory protein ͉ host factor ͉ virion infectivity

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“…To address these issues, we created a conditionally active Nef protein by fusing it to the hormone binding domain of the ER using a strategy similar to one originally reported by Walk et al (32). Structural and biochemical studies have shown that Nef can form dimers and higher-order oligomers (33)(34)(35)(36), which may be important for some signaling functions (32). One effect of ER fusion is to allow regulated dimerization, which may in turn control the functional activity of Nef.…”

Section: Hiv-1 Nef Inhibits Apoptosis Induced By Cytokine Deprivationmentioning

confidence: 99%

HIV-1 Nef Promotes Survival of TF-1 Macrophages by Inducing Bcl-X Expression in an Extracellular Signal-regulated Kinase-dependent Manner

Choi

Smithgall

2004

Journal of Biological Chemistry

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The crystal structure of HIV-1 Nef protein bound to the Fyn kinase SH3 domain suggests a role for this complex in altered T cell receptor signaling

Cited by 201 publications

References 72 publications

Protein–protein interaction inhibition (2P2I) combining high throughput and virtual screening: Application to the HIV-1 Nef protein

Protein–protein interaction inhibition (2P2I) combining high throughput and virtual screening: Application to the HIV-1 Nef protein

Dynamin 2 is required for the enhancement of HIV-1 infectivity by Nef

HIV-1 Nef Promotes Survival of TF-1 Macrophages by Inducing Bcl-X Expression in an Extracellular Signal-regulated Kinase-dependent Manner

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