9GTO

NCS-1 bound to a FDA ligand 1

This is a non-PDB format compatible entry.

Summary for 9GTO

• Entry DOI: 10.2210/pdb9gto/pdb
• Descriptor: Neuronal calcium sensor 1, CALCIUM ION, (5-methyl-2-oxidanylidene-1,3-dioxol-4-yl)methyl 2-ethoxy-3-[[4-[2-(5-oxidanylidene-4~{H}-1,2,4-oxadiazol-3-yl)phenyl]phenyl]methyl]benzimidazole-4-carboxylate, ... (5 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: 1
• Total formula weight: 21388.13

Authors

Munoz-Reyes, D.,Miro-Rodriguez, C.,Sanchez-Barrena, M.J. (deposition date: 2024-09-18, release date: 2025-11-19)

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., 2025

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: 41211723
DOI: 10.1021/acs.jmedchem.5c01626

Experimental method

X-RAY DIFFRACTION (2.3 Å)