Exploring NMR ensembles of calcium binding proteins: Perspectives to design inhibitors of protein-protein interactions
- Equal contributors
1 MTi, Inserm U973 - University Paris Diderot, 35 rue Helene Brion, Bat. Lamarck, 75013 Paris, France
2 Department of Chemistry, West University of Timisoara, 16 Pestalozzi, 300115 Timisoara, Romania
3 Institut Curie Centre de Recherche, Centre Universitaire Paris-Sud, 91405 Orsay cedex, France
4 Inserm U759, Centre Universitaire Paris-Sud, 91405 Orsay cedex, France
BMC Structural Biology 2011, 11:24 doi:10.1186/1472-6807-11-24Published: 12 May 2011
Disrupting protein-protein interactions by small organic molecules is nowadays a promising strategy employed to block protein targets involved in different pathologies. However, structural changes occurring at the binding interfaces make difficult drug discovery processes using structure-based drug design/virtual screening approaches. Here we focused on two homologous calcium binding proteins, calmodulin and human centrin 2, involved in different cellular functions via protein-protein interactions, and known to undergo important conformational changes upon ligand binding.
In order to find suitable protein conformations of calmodulin and centrin for further structure-based drug design/virtual screening, we performed in silico structural/energetic analysis and molecular docking of terphenyl (a mimicking alpha-helical molecule known to inhibit protein-protein interactions of calmodulin) into X-ray and NMR ensembles of calmodulin and centrin. We employed several scoring methods in order to find the best protein conformations. Our results show that docking on NMR structures of calmodulin and centrin can be very helpful to take into account conformational changes occurring at protein-protein interfaces.
NMR structures of protein-protein complexes nowadays available could efficiently be exploited for further structure-based drug design/virtual screening processes employed to design small molecule inhibitors of protein-protein interactions.