6QI4

NCS-1 bound to a ligand

6QI4 の概要

• エントリーDOI: 10.2210/pdb6qi4/pdb
• 分子名称: Neuronal calcium sensor 1, CALCIUM ION, HEXAETHYLENE GLYCOL, ... (9 entities in total)
• 機能のキーワード: calcium sensor, synapse regulation, metal binding protein
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 46323.33

構造登録者

Sanchez-Barrena, M.J.,Blanco-Gabella, P. (登録日: 2019-01-17, 公開日: 2019-07-17, 最終更新日: 2024-01-24)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.78 Å)