6QI4

NCS-1 bound to a ligand

Summary for 6QI4

• Entry DOI: 10.2210/pdb6qi4/pdb
• Descriptor: Neuronal calcium sensor 1, CALCIUM ION, HEXAETHYLENE GLYCOL, ... (9 entities in total)
• Functional Keywords: calcium sensor, synapse regulation, metal binding protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 46323.33

Authors

Sanchez-Barrena, M.J.,Blanco-Gabella, P. (deposition date: 2019-01-17, release date: 2019-07-17, Last modification date: 2024-01-24)

Primary citation

Canal-Martin, A.,Sastre, J.,Sanchez-Barrena, M.J.,Canales, A.,Baldominos, S.,Pascual, N.,Martinez-Gonzalez, L.,Molero, D.,Fernandez-Valle, M.E.,Saez, E.,Blanco-Gabella, P.,Gomez-Rubio, E.,Martin-Santamaria, S.,Saiz, A.,Mansilla, A.,Canada, F.J.,Jimenez-Barbero, J.,Martinez, A.,Perez-Fernandez, R.
Insights into real-time chemical processes in a calcium sensor protein-directed dynamic library.
Nat Commun, 10:2798-2798, 2019

PubMed Abstract: Dynamic combinatorial chemistry (DCC) has proven its potential in drug discovery speeding the identification of modulators of biological targets. However, the exchange chemistries typically take place under specific reaction conditions, with limited tools capable of operating under physiological parameters. Here we report a catalyzed protein-directed DCC working at low temperatures that allows the calcium sensor NCS-1 to find the best ligands in situ. Ultrafast NMR identifies the reaction intermediates of the acylhydrazone exchange, tracing the molecular assemblies and getting a real-time insight into the essence of DCC processes at physiological pH. Additionally, NMR, X-ray crystallography and computational methods are employed to elucidate structural and mechanistic aspects of the molecular recognition event. The DCC approach leads us to the identification of a compound stabilizing the NCS-1/Ric8a complex and whose therapeutic potential is proven in a Drosophila model of disease with synaptic alterations.

PubMed: 31243268
DOI: 10.1038/s41467-019-10627-w

Experimental method

X-RAY DIFFRACTION (1.78 Å)