Molecular modeling and site-directed mutagenesis of CCR5 reveal residues critical for chemokine binding and signal transduction
| Autor: | James W. Hall, Jiansong Luo, Ziwei Huang, Naiming Zhou, Xiaobing Han, Zhaowen Luo |
|---|---|
| Rok vydání: | 2000 |
| Předmět: |
Models
Molecular CCR1 Receptors CCR5 viruses Immunology virus diseases HIV Envelope Protein gp120 Biology Envelope glycoprotein GP120 Cell biology Structure-Activity Relationship Chemokine receptor Biochemistry Chemokine binding Mutagenesis Site-Directed biology.protein Humans Immunology and Allergy Chemokines Signal transduction Site-directed mutagenesis CC chemokine receptors CCL22 Signal Transduction |
| Zdroj: | European Journal of Immunology. 30:164-173 |
| ISSN: | 1521-4141 0014-2980 |
| Popis: | The CC chemokine receptor CCR5 is the receptor for several chemokines and coreceptor for the entry of HIV-1. Whereas many studies focus on CCR5 interaction with HIV-1, residues in CCR5 important for chemokine binding and subsequent signal transduction remain poorly understood. Here we use an approach combining protein structure modeling and site-directed mutagenesis to probe the structure of CCR5 and its interactions with chemokine ligands and HIV-1. Structural models of CCR5 rationalize extensive biological data about the role of CCR5 in HIV-1 envelope glycoprotein gp120 binding and HIV-1 entry. Furthermore, we carry out site-directed mutagenesis guided by structural analysis of the complex of CCR5 and a chemokine. This leads to the novel observation that certain residues, such as Tyr10 and Lys26, in the N terminus of CCR5 play a critical structural role for ligand binding and signaling. Single glycine substitution of these residues significantly decreases chemokine binding and signal transduction. These results provide new insight into the structural basis for CCR5 receptor-ligand interaction and may guide the design of novel inhibitors. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text