Limits...
Exploring NMR ensembles of calcium binding proteins: perspectives to design inhibitors of protein-protein interactions.

Isvoran A, Badel A, Craescu CT, Miron S, Miteva MA - BMC Struct. Biol. (2011)

Bottom Line: 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: MTi, Inserm U973 - University Paris Diderot, 35 rue Helene Brion, Bat, Lamarck, 75013 Paris, France.

ABSTRACT

Background: 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.

Results: 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.

Conclusions: 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.

Show MeSH

Related in: MedlinePlus

Electrostatic potential distribution on the protein surface of the C-terminal domains. (A) CaM; (B) HsCen2. The potential computed using PCE [59] is shown from -3.0 kcal/mol/e (red) to +3.0 kcal/mol/e (blue). The residue numbers correspond to the ones in the NMR files, 2K0F for CaM and 2A4J for HsCen2.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3116463&req=5

Figure 6: Electrostatic potential distribution on the protein surface of the C-terminal domains. (A) CaM; (B) HsCen2. The potential computed using PCE [59] is shown from -3.0 kcal/mol/e (red) to +3.0 kcal/mol/e (blue). The residue numbers correspond to the ones in the NMR files, 2K0F for CaM and 2A4J for HsCen2.

Mentions: The 3D electrostatic potential distribution on the X-ray C-CaM and C-HsCen2 surfaces (see Figure 6) indicates that overall C-CaM is more negatively charged than C-HsCen2; this could be related with the stronger affinity of Ca2+ for CaM than HsCen2 [48]. This observation is also valid for the binding zone of the C-CaM and C-HsCen2. The presence of a large number of negatively charged residues in both proteins, and especially in C-CaM, resulted in several computed abnormal pKa values for C-CaM: 7.3 for E100, 8.4 for D129, and 7.6 for E136; for HsCen2: 6.6 for D114 and 7.4 for D154 (these residues are not situated in the binding pocket). The mean local hydrophobic density calculated using Fpocket tool [49] was 41.39 and 54.78 for the binding pockets of C-CaM and C-HsCen2, respectively. Following these results, we can speculate that the higher hydrophobicity of C-HsCen2 binding zone might facilitate a potential binding of the hydrophobic 1-naphthyl terphenyl.


Exploring NMR ensembles of calcium binding proteins: perspectives to design inhibitors of protein-protein interactions.

Isvoran A, Badel A, Craescu CT, Miron S, Miteva MA - BMC Struct. Biol. (2011)

Electrostatic potential distribution on the protein surface of the C-terminal domains. (A) CaM; (B) HsCen2. The potential computed using PCE [59] is shown from -3.0 kcal/mol/e (red) to +3.0 kcal/mol/e (blue). The residue numbers correspond to the ones in the NMR files, 2K0F for CaM and 2A4J for HsCen2.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3116463&req=5

Figure 6: Electrostatic potential distribution on the protein surface of the C-terminal domains. (A) CaM; (B) HsCen2. The potential computed using PCE [59] is shown from -3.0 kcal/mol/e (red) to +3.0 kcal/mol/e (blue). The residue numbers correspond to the ones in the NMR files, 2K0F for CaM and 2A4J for HsCen2.
Mentions: The 3D electrostatic potential distribution on the X-ray C-CaM and C-HsCen2 surfaces (see Figure 6) indicates that overall C-CaM is more negatively charged than C-HsCen2; this could be related with the stronger affinity of Ca2+ for CaM than HsCen2 [48]. This observation is also valid for the binding zone of the C-CaM and C-HsCen2. The presence of a large number of negatively charged residues in both proteins, and especially in C-CaM, resulted in several computed abnormal pKa values for C-CaM: 7.3 for E100, 8.4 for D129, and 7.6 for E136; for HsCen2: 6.6 for D114 and 7.4 for D154 (these residues are not situated in the binding pocket). The mean local hydrophobic density calculated using Fpocket tool [49] was 41.39 and 54.78 for the binding pockets of C-CaM and C-HsCen2, respectively. Following these results, we can speculate that the higher hydrophobicity of C-HsCen2 binding zone might facilitate a potential binding of the hydrophobic 1-naphthyl terphenyl.

Bottom Line: 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: MTi, Inserm U973 - University Paris Diderot, 35 rue Helene Brion, Bat, Lamarck, 75013 Paris, France.

ABSTRACT

Background: 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.

Results: 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.

Conclusions: 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.

Show MeSH
Related in: MedlinePlus