9gu8

From Proteopedia

NCS-1 bound to a FDA ligand 4

Structural highlights

9gu8 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.67Å
Ligands:	, , , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

NCS1_HUMAN Neuronal calcium sensor, regulator of G protein-coupled receptor phosphorylation in a calcium dependent manner. Directly regulates GRK1 (RHOK), but not GRK2 to GRK5. Can substitute for calmodulin (By similarity). Stimulates PI4KB kinase activity (By similarity). Involved in long-term synaptic plasticity through its interaction with PICK1 (By similarity). May also play a role in neuron differentiation through inhibition of the activity of N-type voltage-gated calcium channel (By similarity).

Publication Abstract from PubMed

Dopamine D(2) receptor (D(2)R) 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 D(2)R in a Ca(2+)-dependent manner. Using in vitro and cellular assays, we found that NCS-1 promotes D(2)R 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/D(2)R interface. Azilsartan medoxomil, atorvastatin, and vilazodone disrupt this interaction, reducing D(2)R surface expression. Structural studies revealed that these compounds target NCS-1, overlap the D(2)R binding site, and perturb the dynamics of the regulatory helix H10. These findings reveal an unexploited intracellular mechanism to modulate D(2)R function via PPI modulation, offering a novel strategy to fine-tune dopaminergic tone beyond receptor blockade or direct agonism.

FDA Drug Repurposing Uncovers Modulators of Dopamine D(2) Receptor Localization via Disruption of the NCS-1 Interaction.,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 NE, Mansilla A, Sanchez-Barrena MJ J Med Chem. 2025 Nov 10. doi: 10.1021/acs.jmedchem.5c01626. PMID:41211723^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Muñoz-Reyes D, Aguado L, Arroyo-Urea S, Requena C, Pérez-Suárez S, Sánchez-Yepes S, Argerich J, Miró-Rodríguez C, Ulzurrun E, Rodríguez-Martín E, García-Nafría J, Campillo NE, Mansilla A, Sánchez-Barrena MJ. FDA Drug Repurposing Uncovers Modulators of Dopamine D(2) Receptor Localization via Disruption of the NCS-1 Interaction. J Med Chem. 2025 Nov 10. PMID:41211723 doi:10.1021/acs.jmedchem.5c01626