The regulation of the NCS-1 mediated protein/protein interactions with small molecules with therapeutic potential in neuronal disease
Protein Structure and Function
Instituto de Química Física "Rocasolano" CSIC (IQFR)
DESCRIPTION OF THE OFFER
The Ca2+ sensing protein neuronal calcium sensor 1 (NCS-1) plays key roles in the regulation of neuronal function through the interaction with different target proteins. Among them, NCS-1 regulates G-protein coupled receptors (Dopamine D2 and Cannabinoid CB1) and G-protein activators such as Ric8a. These proteins are pharmacological targets and their function is affected in a whole range of synaptopathies such as neurodevelopmental disorders (Autism, Fragile X syndrome) and neurodegenerative diseases (Parkinson, Huntington, Alzheimer). Recently, we have demonstrated the druggability of the NCS-1/Ric8a interface. We have shown that it is possible to inhibit this protein complex with small molecules to restores normal synapse number and associative learning in a Fragile X Syndrome. Conversely, enhancing this protein complex permits to increase synapse number and improve certain phenotypes associated with Alzheimer´s disease. Following the same idea, we would like to regulate GPCR function (Dopamine D2 and Cannobinoid CB1) by regulating their interaction with NCS-1with drug-like compounds to discover the molecular function of NCS-1 on these relevant pharmacological targets and find a therapeutic potential. For this, we intend to carry out crystallographic, computational, biochemical and biophysical studies on these protein-protein complexes.
Biomolecules & Cell D.
Mª José Sánchez Barrena