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Insights to ligand binding to the monoamine transporters-from homology modeling to LeuBAT and dDAT.

Koldsø H, Grouleff J, Schiøtt B - Front Pharmacol (2015)

Bottom Line: Various studies have revealed experimentally validated binding modes of numerous ligands to the BATs using homology modeling.Here we examine and discuss the similarities between the binding models of substrates, antidepressants, psychostimulants, and mazindol in homology models of the human BATs and the recently published crystal structures of the Drosophila dopamine transporter and the engineered protein, LeuBAT.The comparison reveals that careful computational modeling combined with experimental data can be utilized to predict binding of molecules to proteins that agree very well with crystal structures.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, University of Oxford , Oxford, UK ; inSPIN and iNANO Centers, Department of Chemistry, Aarhus University , Aarhus C, Denmark.

ABSTRACT
Understanding of drug binding to the human biogenic amine transporters (BATs) is essential to explain the mechanism of action of these pharmaceuticals but more importantly to be able to develop new and improved compounds to be used in the treatment of depression or drug addiction. Until recently no high resolution structure was available of the BATs and homology modeling was a necessity. Various studies have revealed experimentally validated binding modes of numerous ligands to the BATs using homology modeling. Here we examine and discuss the similarities between the binding models of substrates, antidepressants, psychostimulants, and mazindol in homology models of the human BATs and the recently published crystal structures of the Drosophila dopamine transporter and the engineered protein, LeuBAT. The comparison reveals that careful computational modeling combined with experimental data can be utilized to predict binding of molecules to proteins that agree very well with crystal structures.

No MeSH data available.


Related in: MedlinePlus

Similarities in dDAT and hDAT structures and substrate binding. (A) The overall structure of dDAT (Wang et al., 2015) and the homology model of hDAT (Koldsø et al., 2013b) based on an outward occluded LeuT structure are almost identical with the largest difference being in TM12 where a kink is observed within the dDAT structure. (B) Comparison of the binding mode of the substrate dopamine (DA) within the dDAT crystal structure (gray; Wang et al., 2015) and two binding modes obtained from modeling (Koldsø et al., 2013b) shown in light and dark blue. Italic residue numbers are from the hDAT homology model and normal labels belong to dDAT. (C) Comparison of the binding mode of the substrate DA within the dDAT crystal structure (gray; Wang et al., 2015) and the substrate norepinephrine (NE) in two binding modes obtained from homology model of hNET (Koldsø et al., 2013b) with the models shown in light and dark green. Italic residue numbers are from the hNET homology model. (D) Comparison of the binding mode of the substrate DA within the dDAT crystal structure (gray; Wang et al., 2015) and the substrate serotonin (5-HT) in the experimental validated binding mode within a homology model of hSERT (Koldsø et al., 2013b) with the model shown in pink. Italic residue numbers are from the hSERT homology model.
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Figure 1: Similarities in dDAT and hDAT structures and substrate binding. (A) The overall structure of dDAT (Wang et al., 2015) and the homology model of hDAT (Koldsø et al., 2013b) based on an outward occluded LeuT structure are almost identical with the largest difference being in TM12 where a kink is observed within the dDAT structure. (B) Comparison of the binding mode of the substrate dopamine (DA) within the dDAT crystal structure (gray; Wang et al., 2015) and two binding modes obtained from modeling (Koldsø et al., 2013b) shown in light and dark blue. Italic residue numbers are from the hDAT homology model and normal labels belong to dDAT. (C) Comparison of the binding mode of the substrate DA within the dDAT crystal structure (gray; Wang et al., 2015) and the substrate norepinephrine (NE) in two binding modes obtained from homology model of hNET (Koldsø et al., 2013b) with the models shown in light and dark green. Italic residue numbers are from the hNET homology model. (D) Comparison of the binding mode of the substrate DA within the dDAT crystal structure (gray; Wang et al., 2015) and the substrate serotonin (5-HT) in the experimental validated binding mode within a homology model of hSERT (Koldsø et al., 2013b) with the model shown in pink. Italic residue numbers are from the hSERT homology model.

Mentions: The structure of the dDAT protein compared to a homology model of the human DAT previously published (Koldsø et al., 2013b) is shown in Figure 1A. The general agreement between the homology model of hDAT and the crystal structure of dDAT is very good and the principal differences are observed within TM12, which is slightly kinked in the dDAT structure. One of the largest differences observed between LeuT and dDAT is also TM12 as described previously (Penmatsa et al., 2013) and the differences observed here is therefore not surprising since the hDAT model has been based on the LeuT structure, in which TM12 is not kinked.


Insights to ligand binding to the monoamine transporters-from homology modeling to LeuBAT and dDAT.

Koldsø H, Grouleff J, Schiøtt B - Front Pharmacol (2015)

Similarities in dDAT and hDAT structures and substrate binding. (A) The overall structure of dDAT (Wang et al., 2015) and the homology model of hDAT (Koldsø et al., 2013b) based on an outward occluded LeuT structure are almost identical with the largest difference being in TM12 where a kink is observed within the dDAT structure. (B) Comparison of the binding mode of the substrate dopamine (DA) within the dDAT crystal structure (gray; Wang et al., 2015) and two binding modes obtained from modeling (Koldsø et al., 2013b) shown in light and dark blue. Italic residue numbers are from the hDAT homology model and normal labels belong to dDAT. (C) Comparison of the binding mode of the substrate DA within the dDAT crystal structure (gray; Wang et al., 2015) and the substrate norepinephrine (NE) in two binding modes obtained from homology model of hNET (Koldsø et al., 2013b) with the models shown in light and dark green. Italic residue numbers are from the hNET homology model. (D) Comparison of the binding mode of the substrate DA within the dDAT crystal structure (gray; Wang et al., 2015) and the substrate serotonin (5-HT) in the experimental validated binding mode within a homology model of hSERT (Koldsø et al., 2013b) with the model shown in pink. Italic residue numbers are from the hSERT homology model.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4585151&req=5

Figure 1: Similarities in dDAT and hDAT structures and substrate binding. (A) The overall structure of dDAT (Wang et al., 2015) and the homology model of hDAT (Koldsø et al., 2013b) based on an outward occluded LeuT structure are almost identical with the largest difference being in TM12 where a kink is observed within the dDAT structure. (B) Comparison of the binding mode of the substrate dopamine (DA) within the dDAT crystal structure (gray; Wang et al., 2015) and two binding modes obtained from modeling (Koldsø et al., 2013b) shown in light and dark blue. Italic residue numbers are from the hDAT homology model and normal labels belong to dDAT. (C) Comparison of the binding mode of the substrate DA within the dDAT crystal structure (gray; Wang et al., 2015) and the substrate norepinephrine (NE) in two binding modes obtained from homology model of hNET (Koldsø et al., 2013b) with the models shown in light and dark green. Italic residue numbers are from the hNET homology model. (D) Comparison of the binding mode of the substrate DA within the dDAT crystal structure (gray; Wang et al., 2015) and the substrate serotonin (5-HT) in the experimental validated binding mode within a homology model of hSERT (Koldsø et al., 2013b) with the model shown in pink. Italic residue numbers are from the hSERT homology model.
Mentions: The structure of the dDAT protein compared to a homology model of the human DAT previously published (Koldsø et al., 2013b) is shown in Figure 1A. The general agreement between the homology model of hDAT and the crystal structure of dDAT is very good and the principal differences are observed within TM12, which is slightly kinked in the dDAT structure. One of the largest differences observed between LeuT and dDAT is also TM12 as described previously (Penmatsa et al., 2013) and the differences observed here is therefore not surprising since the hDAT model has been based on the LeuT structure, in which TM12 is not kinked.

Bottom Line: Various studies have revealed experimentally validated binding modes of numerous ligands to the BATs using homology modeling.Here we examine and discuss the similarities between the binding models of substrates, antidepressants, psychostimulants, and mazindol in homology models of the human BATs and the recently published crystal structures of the Drosophila dopamine transporter and the engineered protein, LeuBAT.The comparison reveals that careful computational modeling combined with experimental data can be utilized to predict binding of molecules to proteins that agree very well with crystal structures.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, University of Oxford , Oxford, UK ; inSPIN and iNANO Centers, Department of Chemistry, Aarhus University , Aarhus C, Denmark.

ABSTRACT
Understanding of drug binding to the human biogenic amine transporters (BATs) is essential to explain the mechanism of action of these pharmaceuticals but more importantly to be able to develop new and improved compounds to be used in the treatment of depression or drug addiction. Until recently no high resolution structure was available of the BATs and homology modeling was a necessity. Various studies have revealed experimentally validated binding modes of numerous ligands to the BATs using homology modeling. Here we examine and discuss the similarities between the binding models of substrates, antidepressants, psychostimulants, and mazindol in homology models of the human BATs and the recently published crystal structures of the Drosophila dopamine transporter and the engineered protein, LeuBAT. The comparison reveals that careful computational modeling combined with experimental data can be utilized to predict binding of molecules to proteins that agree very well with crystal structures.

No MeSH data available.


Related in: MedlinePlus