Linking non-peptide ligand binding mode to activity at the human cholecystokinin-2 receptor
| Autor: | Caroline Low, Daniel Fourmy, Barret Kalindjian, Magali Foucaud, Esther Marco, Chantal Escrieut |
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| Přispěvatelé: | Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), the James Black Foundation, James Black Foundation, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Simon, Marie Francoise |
| Rok vydání: | 2008 |
| Předmět: |
Models
Molecular Stereochemistry MESH: Protein Structure Secondary Ligands Biochemistry Partial agonist MESH: Receptor Cholecystokinin B Protein Structure Secondary 03 medical and health sciences 0302 clinical medicine [SDV.BBM] Life Sciences [q-bio]/Biochemistry Molecular Biology MESH: Ligands Moiety Inverse agonist Humans [SDV.BBM]Life Sciences [q-bio]/Biochemistry Molecular Biology Binding site Receptor Molecular Biology 030304 developmental biology 0303 health sciences MESH: Humans Binding Sites Chemistry Cell Biology Ligand (biochemistry) Receptor Cholecystokinin B 3. Good health MESH: Binding Sites 030220 oncology & carcinogenesis Helix Cholecystokinin B receptor MESH: Models Molecular |
| Zdroj: | Journal of Biological Chemistry Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, 2008, 283 (51), pp.35860-8. ⟨10.1074/jbc.M805513200⟩ Journal of Biological Chemistry, 2008, 283 (51), pp.35860-8. ⟨10.1074/jbc.M805513200⟩ |
| ISSN: | 0021-9258 1083-351X |
| Popis: | International audience; Given the importance of G-protein-coupled receptors as pharmacological targets in medicine, efforts directed at the understanding the molecular mechanism by which pharmacological compounds regulate their activity is of paramount importance. Here, we investigated at an atomic level the mechanism of inverse agonism and partial agonism of two high affinity, high selectivity very similar non-peptide ligands of the cholecystokinin-2 receptor (CCK2R) which differ by the absence or presence of a methyl group on their indole moiety. Using in silico, site-directed mutagenesis and pharmacological experiments, we demonstrated that these functionally different activities are due to differing anchoring modes of the two compounds to a residue of helix II (Thr-2.61) in the inactive state of the CCK2R. The binding mode of the inverse agonist allows the ligand to interact through its phenyl moiety with a key amino acid for CCK2R activation (Trp-6.48), preventing rotation of helix VI and, thus, CCK2R activation, whereas the partial agonist binds deeper into the binding pocket and closer to helix V, so that CCK2R activation is favored. This study on the molecular mechanism of ligand action opens the possibility of target-based optimization of G protein-coupled receptor non-peptide ligands. |
| Databáze: | OpenAIRE |
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