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

Sequence and structural homology of calmodulin and centrin. (A) sequence alignment of CaM and HsCen2, the C-terminal domains are shown in blue and the pocket regions in magenta; (B) superposition of the X-ray structures of CaM (yellow cartoon, unbound form, code 1CLL) and HsCen2 (blue cartoon, bound form, code 2GGM); (C) CaM in a complex with trifluorperasine (sticks in magenta) (code 1LIN); (D) structure of HsCen2 (unbound form, code 1M39). The blue region corresponds to the C-domain of HsCen2; the helix (in cyan) belongs to the N-terminal domain.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Sequence and structural homology of calmodulin and centrin. (A) sequence alignment of CaM and HsCen2, the C-terminal domains are shown in blue and the pocket regions in magenta; (B) superposition of the X-ray structures of CaM (yellow cartoon, unbound form, code 1CLL) and HsCen2 (blue cartoon, bound form, code 2GGM); (C) CaM in a complex with trifluorperasine (sticks in magenta) (code 1LIN); (D) structure of HsCen2 (unbound form, code 1M39). The blue region corresponds to the C-domain of HsCen2; the helix (in cyan) belongs to the N-terminal domain.

Mentions: We exploit here docking of 1-naphthyl terphenyl (see Figure 1) into two homologous Ca2+-binding proteins, CaM and human centrin 2 (HsCen2), to find out the CaM and HsCen2 conformations that could efficiently be employed for further structure-based design of inhibitors of PPIs. CaM and HsCen2 have a high sequence homology (Figure 2A) and display a structural similarity as both proteins are composed by two EF-hand N- and C-terminal domains connected by a helical linker (see Figure 2B). The binding of 1-naphthyl terphenyl by CaM (IC50 = 9 nM) has already been shown experimentally [12]. Following the strong similarity between the two Ca2+-binding proteins we probe in this study a potential terphenyl binding into HsCen2.


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)

Sequence and structural homology of calmodulin and centrin. (A) sequence alignment of CaM and HsCen2, the C-terminal domains are shown in blue and the pocket regions in magenta; (B) superposition of the X-ray structures of CaM (yellow cartoon, unbound form, code 1CLL) and HsCen2 (blue cartoon, bound form, code 2GGM); (C) CaM in a complex with trifluorperasine (sticks in magenta) (code 1LIN); (D) structure of HsCen2 (unbound form, code 1M39). The blue region corresponds to the C-domain of HsCen2; the helix (in cyan) belongs to the N-terminal domain.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Sequence and structural homology of calmodulin and centrin. (A) sequence alignment of CaM and HsCen2, the C-terminal domains are shown in blue and the pocket regions in magenta; (B) superposition of the X-ray structures of CaM (yellow cartoon, unbound form, code 1CLL) and HsCen2 (blue cartoon, bound form, code 2GGM); (C) CaM in a complex with trifluorperasine (sticks in magenta) (code 1LIN); (D) structure of HsCen2 (unbound form, code 1M39). The blue region corresponds to the C-domain of HsCen2; the helix (in cyan) belongs to the N-terminal domain.
Mentions: We exploit here docking of 1-naphthyl terphenyl (see Figure 1) into two homologous Ca2+-binding proteins, CaM and human centrin 2 (HsCen2), to find out the CaM and HsCen2 conformations that could efficiently be employed for further structure-based design of inhibitors of PPIs. CaM and HsCen2 have a high sequence homology (Figure 2A) and display a structural similarity as both proteins are composed by two EF-hand N- and C-terminal domains connected by a helical linker (see Figure 2B). The binding of 1-naphthyl terphenyl by CaM (IC50 = 9 nM) has already been shown experimentally [12]. Following the strong similarity between the two Ca2+-binding proteins we probe in this study a potential terphenyl binding into HsCen2.

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