9GU6
NCS-1 bound to FDA ligand 3
Summary for 9GU6
| Entry DOI | 10.2210/pdb9gu6/pdb |
| Descriptor | Neuronal calcium sensor 1, CALCIUM ION, 7-[2-(4-FLUORO-PHENYL)-5-ISOPROPYL-3-PHENYL-4-PHENYLCARBAMOYL-PYRROL-1-YL]- 3,5-DIHYDROXY-HEPTANOIC ACID, ... (9 entities in total) |
| Functional Keywords | neuronal calcium sensor 1, ef-hand containing protein, drug repurposing, fda ligand, metal binding protein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 4 |
| Total formula weight | 93970.90 |
| Authors | Munoz-Reyes, D.,Sanchez-Barrena, M.J. (deposition date: 2024-09-19, release date: 2025-11-19, Last modification date: 2025-12-10) |
| Primary citation | Munoz-Reyes, D.,Aguado, L.,Arroyo-Urea, S.,Requena, C.,Perez-Suarez, S.,Sanchez-Yepes, S.,Argerich, J.,Miro-Rodriguez, C.,Ulzurrun, E.,Rodriguez-Martin, E.,Garcia-Nafria, J.,Campillo, N.E.,Mansilla, A.,Sanchez-Barrena, M.J. FDA Drug Repurposing Uncovers Modulators of Dopamine D 2 Receptor Localization via Disruption of the NCS-1 Interaction. J.Med.Chem., 68:23993-24010, 2025 Cited by PubMed Abstract: Dopamine D receptor (DR) regulates key aspects of motor control, cognition, and reward. Its function depends not only on ligand binding and signaling efficacy but also on the dynamic control of receptor localization at the cell surface. Neuronal calcium sensor 1 (NCS-1) interacts with DR in a Ca-dependent manner. Using in vitro and cellular assays, we found that NCS-1 promotes DR trafficking to the plasma membrane through active exocytosis while preserving canonical receptor pharmacology. A screen of FDA-approved drugs identified protein-protein interaction (PPI) modulators targeting the NCS-1/DR interface. Azilsartan medoxomil, atorvastatin, and vilazodone disrupt this interaction, reducing DR surface expression. Structural studies revealed that these compounds target NCS-1, overlap the DR binding site, and perturb the dynamics of the regulatory helix H10. These findings reveal an unexploited intracellular mechanism to modulate DR function via PPI modulation, offering a novel strategy to fine-tune dopaminergic tone beyond receptor blockade or direct agonism. PubMed: 41211723DOI: 10.1021/acs.jmedchem.5c01626 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.93 Å) |
Structure validation
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