| Structures determined by the
Macromolecular Crystallography Laboratory,
Protein Structure Section at the NCI-Frederick campus.
Work performed in collaboration with the
Skalka Laboratory in the Institute for Cancer Research,
Fox Chase Cancer Center, and with the Laboratory of Molecular Pharmacology and the Laboratory of Medicinal Chemistry, Division of
Basic Sciences, NCI, NIH. |
Y-1, Y-2, and Y-3 are structurally related inhibitors found by screening chemicals in
the NCI Repository in an assay for HIV-1 antiviral activity. Y-3 exhibits the best inhibition
properties, stopping IN activity about the same level, called IC50,
in both ASV and HIV-1 IN assays. Y-4 was synthesized to help explore the mode of binding of
these inhibitors to INs.
| This view shows the only inhibitor of the set, Y-3, that can be seen bound to ASV IN in an x-ray crystal structure. Two inhibitor molecules are shown bound near the crystallographic two-fold axis between two IN monomers. Inhibitors are shown as small ball-and-stick figures in green, white, and red near the center, with the protein shown as brown, green, and blue ribbons. The IN active site residues only are shown as green, white, and red ball-and-stick figures. *Image courtesy of Dr. Fan Yang, former member of the MCL. |
This model of the Y-3 inhibitor has atoms drawn in various colors (carbon, green; oxygen, red; nitrogen, blue; sulfur, yellow). The electron density map is good enough to show the `hole' in the "A" ring.
Electron density, colored here in blue, is what we "see" when we finish our x-ray crystallography experiments. Then, models of protein or other compounds are fit into the electron density based on what we know (i.e., from what we put into the experimental mixture or from prior biochemical analyses). Sometimes the map is clear enough to show unexpected results: we find other ligands that we did not expect to see bound in the protein crystal, or we can correct prior work such as protein sequencing. Hydrogen atoms do not diffract x-rays well enough to show up in our results, so we cannot draw them in the models. We know they are there, of course.
Note: These inhibitors are not drugs and they are highly toxic. Significant further research must be done in order to increase solubility, increase potency, and reduce toxicity before any chemicals can be considered for human testing or medical use. Many thousands of inhibitors are tested for every one that passes the stringent tests required before an inhibitor can be used as a drug.
Click here for a look at interactions
between the ASV IN flexible loop and Y-3 inhibitor.
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