The Amino-Terminus of Angiotensin II Contacts Several Ectodomains of the Angiotensin II Receptor AT1
| Autor: | Gaétan Guillemette, Luta Luse Basambombo, Richard Leduc, Guillaume Lemieux, Dany Fillion, Pierre Lavigne, Emanuel Escher |
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| Rok vydání: | 2010 |
| Předmět: |
Angiotensin receptor
Stereochemistry Molecular Sequence Data Photoaffinity Labels Binding Competitive Receptor Angiotensin Type 1 Inhibitory Concentration 50 Structure-Activity Relationship Cell surface receptor Chlorocebus aethiops Drug Discovery Animals Humans Amino Acid Sequence Receptor Peptide sequence G protein-coupled receptor Binding Sites Angiotensin II receptor type 1 Photoaffinity labeling Chemistry Angiotensin II Biochemistry COS Cells Mutagenesis Site-Directed Molecular Medicine Electrophoresis Polyacrylamide Gel hormones hormone substitutes and hormone antagonists |
| Zdroj: | Journal of Medicinal Chemistry. 53:2063-2075 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors and major targets for drug development. Herein, we sought to identify the regions of the human angiotensin II (AngII) type 1 (hAT(1)) receptor binding cleft that interact with all positions of the AngII using photoaffinity labeling. We conducted a complete iterative walk-through of the AngII sequence with either p-benzoyl-L-phenylalanine (Bpa) or p-[3-(trifluoromethyl)-3H-diazirin-3-yl]-L-phenylalanine (Tdf) to yield two series of eight photoreactive analogues. Pharmacological properties assessment of these sixteen analogues showed that the CAM receptor has a structure-activity relationship (SAR) more amenable to the amino acid substitutions at positions 1, 2, 3, and 5 of AngII than the WT receptor. Photoaffinity labeling of the CAM receptor with the selected analogues, which exhibit different but complementary photochemical properties, suggested that the AngII amino-terminus resides in a hydrophilic environment and interacts simultaneously with different regions of the hAT(1) receptor, including several ectodomains. |
| Databáze: | OpenAIRE |
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