| Literature DB >> 16494916 |
Christoph Seibert1, Weiwen Ying, Svetlana Gavrilov, Fotini Tsamis, Shawn E Kuhmann, Anandan Palani, Jayaram R Tagat, John W Clader, Stuart W McCombie, Bahige M Baroudy, Steven O Smith, Tatjana Dragic, John P Moore, Thomas P Sakmar.
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.Entities:
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Year: 2006 PMID： 16494916 DOI： 10.1016/j.virol.2006.01.018
Source DB: PubMed Journal: Virology ISSN： 0042-6822 Impact factor: 3.616