Interaction of small molecule inhibitors of HIV-1 entry with CCR5
| Autor: | Stuart W. McCombie, Thomas P. Sakmar, Tatjana Dragic, Fotini Tsamis, Bahige M. Baroudy, Christoph Seibert, John W. Clader, John P. Moore, Anandan Palani, Svetlana Gavrilov, Shawn E. Kuhmann, Jayaram R. Tagat, Steven O. Smith, Weiwen Ying |
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| Rok vydání: | 2006 |
| Předmět: |
Models
Molecular Receptors CCR5 Pyridines viruses Biology Protein Structure Secondary Cell Line Cyclic N-Oxides 03 medical and health sciences GPCR Protein structure Piperidines HIV Fusion Inhibitors Viral entry Virology Oximes Humans CCR5 inhibitors SCH-C Homology modeling TAK-779 030304 developmental biology G protein-coupled receptor chemistry.chemical_classification 0303 health sciences Binding Sites Molecular Structure 030302 biochemistry & molecular biology AD101 Rational design virus diseases Amides Small molecule 3. Good health Amino acid Quaternary Ammonium Compounds Biochemistry chemistry Chemokine binding Mutagenesis Site-Directed HIV-1 CCR5 |
| Zdroj: | Virology. 349(1):41-54 |
| ISSN: | 0042-6822 |
| DOI: | 10.1016/j.virol.2006.01.018 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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