Interaction of small molecule inhibitors of HIV-1 entry with CCR5 |
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Authors: | Seibert Christoph Ying Weiwen Gavrilov Svetlana Tsamis Fotini Kuhmann Shawn E Palani Anandan Tagat Jayaram R Clader John W McCombie Stuart W Baroudy Bahige M Smith Steven O Dragic Tatjana Moore John P Sakmar Thomas P |
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Affiliation: | Laboratory of Molecular Biology and Biochemistry, The Rockefeller University, New York, NY 10021, USA. seiberc@mail.rockefeller.edu |
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Abstract: | The CC-chemokine receptor 5 (CCR5) is the major coreceptor for macrophage-tropic (R5) HIV-1 strains. Several small molecule inhibitors of CCR5 that block chemokine binding and HIV-1 entry are being evaluated as drug candidates. Here we define how CCR5 antagonists TAK-779, AD101 (SCH-350581) and SCH-C (SCH-351125), which inhibit HIV-1 entry, interact with CCR5. Using a mutagenesis approach in combination with a viral entry assay to provide a direct functional read out, we tested predictions based on a homology model of CCR5 and analyzed the functions of more than 30 amino acid residues. We find that a key set of aromatic and aliphatic residues serves as a hydrophobic core for the ligand binding pocket, while E283 is critical for high affinity interaction, most likely by acting as the counterion for a positively charged nitrogen atom common to all three inhibitors. These results provide a structural basis for understanding how specific antagonists interact with CCR5, and may be useful for the rational design of new, improved CCR5 ligands. |
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Keywords: | GPCR CCR5 CCR5 inhibitors HIV-1 TAK-779 AD101 SCH-C |
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