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Molecular modeling reveals the novel inhibition mechanism and binding mode of three natural compounds to staphylococcal α-hemolysin.

Qiu J, Wang D, Zhang Y, Dong J, Wang J, Niu X - PLoS ONE (2013)

Bottom Line: This was completed using conventional Molecular Dynamics (MD) simulations.This novel inhibition mechanism has been confirmed by both the steered MD simulations and the experimental data obtained from a deoxycholate-induced oligomerization assay.This study can facilitate the design of new antibacterial drugs against S. aureus.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Zoonosis, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, China.

ABSTRACT
α-Hemolysin (α-HL) is a self-assembling, channel-forming toxin that is produced as a soluble monomer by Staphylococcus aureus strains. Until now, α-HL has been a significant virulence target for the treatment of S. aureus infection. In our previous report, we demonstrated that some natural compounds could bind to α-HL. Due to the binding of those compounds, the conformational transition of α-HL from the monomer to the oligomer was blocked, which resulted in inhibition of the hemolytic activity of α-HL. However, these results have not indicated how the binding of the α-HL inhibitors influence the conformational transition of the whole protein during the oligomerization process. In this study, we found that three natural compounds, Oroxylin A 7-O-glucuronide (OLG), Oroxin A (ORA), and Oroxin B (ORB), when inhibiting the hemolytic activity of α-HL, could bind to the "stem" region of α-HL. This was completed using conventional Molecular Dynamics (MD) simulations. By interacting with the novel binding sites of α-HL, the ligands could form strong interactions with both sides of the binding cavity. The results of the principal component analysis (PCA) indicated that because of the inhibitors that bind to the "stem" region of α-HL, the conformational transition of α-HL from the monomer to the oligomer was restricted. This caused the inhibition of the hemolytic activity of α-HL. This novel inhibition mechanism has been confirmed by both the steered MD simulations and the experimental data obtained from a deoxycholate-induced oligomerization assay. This study can facilitate the design of new antibacterial drugs against S. aureus.

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Detailed inhibitor-induced inhibition activation mechanism of α-HL.The inhibitors OLG, ORA and ORB can bind to the “stem” domain of α-HL by interactions with Tyr102/Pro103/Arg104/Tyr112 and Gly126. The ligands can form strong interactions with both sides of the binding cavity. Because of the ligands binding with the “stem” domain of α-HL, the conformational transition of α-HL from the monomeric α-HL to the oligomer was restricted, which leads to the inhibition of the hemolytic activity of α-HL.
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pone-0080197-g010: Detailed inhibitor-induced inhibition activation mechanism of α-HL.The inhibitors OLG, ORA and ORB can bind to the “stem” domain of α-HL by interactions with Tyr102/Pro103/Arg104/Tyr112 and Gly126. The ligands can form strong interactions with both sides of the binding cavity. Because of the ligands binding with the “stem” domain of α-HL, the conformational transition of α-HL from the monomeric α-HL to the oligomer was restricted, which leads to the inhibition of the hemolytic activity of α-HL.

Mentions: The abundant conformations obtained in the MD simulations provide an opportunity to explore the motion properties of α-HL. Using PCA, we found a strong extended motion in the “stem” domain of the unliganded α-HL. Interestingly, compared with the structure of α-HL in the heptamer determined using X-ray crystallography [22], the “stem” domain must only complete the transition from curl to extend when α-HL changes from a monomer to a heptamer, as shown in Figure 10. Therefore, this conformational motion more meets the need of the conformational transition of α-HL from the monomeric α-HL to the oligomer. However, in the PCA analysis of α-HL-OLG, the motion of the “stem” domain is obviously weaker, which arises from the binding of the ligands, as shown in Figure 8. Then, the “stem” domain of α-HL-OLG cannot complete the transition from curl to extend, which causes the conformational transition of α-HL to be restrained, as shown in Figure 10. Because of the mentioned result, inhibitors can form strong interactions with both sides of the binding cavity of α-HL, which leads to the constraint of the “stem” domain.


Molecular modeling reveals the novel inhibition mechanism and binding mode of three natural compounds to staphylococcal α-hemolysin.

Qiu J, Wang D, Zhang Y, Dong J, Wang J, Niu X - PLoS ONE (2013)

Detailed inhibitor-induced inhibition activation mechanism of α-HL.The inhibitors OLG, ORA and ORB can bind to the “stem” domain of α-HL by interactions with Tyr102/Pro103/Arg104/Tyr112 and Gly126. The ligands can form strong interactions with both sides of the binding cavity. Because of the ligands binding with the “stem” domain of α-HL, the conformational transition of α-HL from the monomeric α-HL to the oligomer was restricted, which leads to the inhibition of the hemolytic activity of α-HL.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3842302&req=5

pone-0080197-g010: Detailed inhibitor-induced inhibition activation mechanism of α-HL.The inhibitors OLG, ORA and ORB can bind to the “stem” domain of α-HL by interactions with Tyr102/Pro103/Arg104/Tyr112 and Gly126. The ligands can form strong interactions with both sides of the binding cavity. Because of the ligands binding with the “stem” domain of α-HL, the conformational transition of α-HL from the monomeric α-HL to the oligomer was restricted, which leads to the inhibition of the hemolytic activity of α-HL.
Mentions: The abundant conformations obtained in the MD simulations provide an opportunity to explore the motion properties of α-HL. Using PCA, we found a strong extended motion in the “stem” domain of the unliganded α-HL. Interestingly, compared with the structure of α-HL in the heptamer determined using X-ray crystallography [22], the “stem” domain must only complete the transition from curl to extend when α-HL changes from a monomer to a heptamer, as shown in Figure 10. Therefore, this conformational motion more meets the need of the conformational transition of α-HL from the monomeric α-HL to the oligomer. However, in the PCA analysis of α-HL-OLG, the motion of the “stem” domain is obviously weaker, which arises from the binding of the ligands, as shown in Figure 8. Then, the “stem” domain of α-HL-OLG cannot complete the transition from curl to extend, which causes the conformational transition of α-HL to be restrained, as shown in Figure 10. Because of the mentioned result, inhibitors can form strong interactions with both sides of the binding cavity of α-HL, which leads to the constraint of the “stem” domain.

Bottom Line: This was completed using conventional Molecular Dynamics (MD) simulations.This novel inhibition mechanism has been confirmed by both the steered MD simulations and the experimental data obtained from a deoxycholate-induced oligomerization assay.This study can facilitate the design of new antibacterial drugs against S. aureus.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Zoonosis, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, China.

ABSTRACT
α-Hemolysin (α-HL) is a self-assembling, channel-forming toxin that is produced as a soluble monomer by Staphylococcus aureus strains. Until now, α-HL has been a significant virulence target for the treatment of S. aureus infection. In our previous report, we demonstrated that some natural compounds could bind to α-HL. Due to the binding of those compounds, the conformational transition of α-HL from the monomer to the oligomer was blocked, which resulted in inhibition of the hemolytic activity of α-HL. However, these results have not indicated how the binding of the α-HL inhibitors influence the conformational transition of the whole protein during the oligomerization process. In this study, we found that three natural compounds, Oroxylin A 7-O-glucuronide (OLG), Oroxin A (ORA), and Oroxin B (ORB), when inhibiting the hemolytic activity of α-HL, could bind to the "stem" region of α-HL. This was completed using conventional Molecular Dynamics (MD) simulations. By interacting with the novel binding sites of α-HL, the ligands could form strong interactions with both sides of the binding cavity. The results of the principal component analysis (PCA) indicated that because of the inhibitors that bind to the "stem" region of α-HL, the conformational transition of α-HL from the monomer to the oligomer was restricted. This caused the inhibition of the hemolytic activity of α-HL. This novel inhibition mechanism has been confirmed by both the steered MD simulations and the experimental data obtained from a deoxycholate-induced oligomerization assay. This study can facilitate the design of new antibacterial drugs against S. aureus.

Show MeSH
Related in: MedlinePlus