6EPA
Structure of dNCS-1 bound to the NCS-1/Ric8a protein/protein interaction regulator IGS-1.76
Summary for 6EPA
| Entry DOI | 10.2210/pdb6epa/pdb |
| Descriptor | FI18190p1, CALCIUM ION, ~{N}-(1,3-benzothiazol-2-yl)-3,3-diphenyl-propanamide, ... (6 entities in total) |
| Functional Keywords | calcium sensor, synapse regulation, signaling protein |
| Biological source | Drosophila melanogaster (Fruit fly) |
| Total number of polymer chains | 1 |
| Total formula weight | 22544.27 |
| Authors | Sanchez-Barrena, M.J.,Daniel, M.,Infantes, L. (deposition date: 2017-10-11, release date: 2018-08-29, Last modification date: 2024-01-17) |
| Primary citation | Roca, C.,Martinez-Gonzalez, L.,Daniel-Mozo, M.,Sastre, J.,Infantes, L.,Mansilla, A.,Chaves-Sanjuan, A.,Gonzalez-Rubio, J.M.,Gil, C.,Canada, F.J.,Martinez, A.,Sanchez-Barrena, M.J.,Campillo, N.E. Deciphering the Inhibition of the Neuronal Calcium Sensor 1 and the Guanine Exchange Factor Ric8a with a Small Phenothiazine Molecule for the Rational Generation of Therapeutic Synapse Function Regulators. J. Med. Chem., 61:5910-5921, 2018 Cited by PubMed Abstract: Protein-protein interactions (PPIs) are known to play an essential role between the neuronal calcium sensor 1 (NCS-1) and the guanine exchange factor Ric8a to regulate synapse function, emerging as a druggable interface for synaptopathies such as the fragile X syndrome (FXS). Recently, the phenothiazine FD44 has been identified as an inhibitor of this PPI, decreasing the abnormally high synapse number and enhancing associative learning in a FXS animal model. Here, we have integrated advanced experimental and computational studies to obtain important structural insights into Drosophila NCS-1/FD44 recognition to understand the basis of its affinity and specificity and generate improved PPI regulators. This has allowed the identification of a new small drug-like molecule, IGS-1.76, which efficiently inhibits the human NCS-1/Ric8a complex with improved binding potency. The crystal structure of the Drosophila NCS-1/IGS-1.76 complex demonstrates that the new inhibitor, although chemically different from FD44, shares the same mechanism of action and constitutes a new hit candidate for FXS. PubMed: 29966094DOI: 10.1021/acs.jmedchem.8b00088 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.82 Å) |
Structure validation
Download full validation report
