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Modeling of the OX1R-orexin-A complex suggests two alternative binding modes.

Karhu L, Turku A, Xhaard H - BMC Struct. Biol. (2015)

Bottom Line: However, a better understanding of specific pairwise interactions would benefit small molecule discovery.We present two binding modes for orexin-A into orexin 1 receptor, which help rationalize previous results from site-directed mutagenesis studies.The binding modes should serve small molecule discovery, and offer insights into the mechanism of receptor activation.

View Article: PubMed Central - PubMed

Affiliation: Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, 00014, Helsinki, Finland. lasse.karhu@helsinki.fi.

ABSTRACT

Background: Interactions between the orexin peptides and their cognate OX1 and OX2 receptors remain poorly characterized. Site-directed mutagenesis studies on orexin peptides and receptors have indicated amino acids important for ligand binding and receptor activation. However, a better understanding of specific pairwise interactions would benefit small molecule discovery.

Results: We constructed a set of three-dimensional models of the orexin 1 receptor based on the 3D-structures of the orexin 2 receptor (released while this manuscript was under review), neurotensin receptor 1 and chemokine receptor CXCR4, conducted an exhaustive docking of orexin-A16-33 peptide fragment with ZDOCK and RDOCK, and analyzed a total of 4301 complexes through multidimensional scaling and clustering. The best docking poses reveal two alternative binding modes, where the C-terminus of the peptide lies deep in the binding pocket, on average about 5-6 Å above Tyr(6.48) and close to Gln(3.32). The binding modes differ in the about 100° rotation of the peptide; the peptide His26 faces either the receptor's fifth transmembrane helix or the seventh helix. Both binding modes are well in line with previous mutation studies and partake in hydrogen bonding similar to suvorexant.

Conclusions: We present two binding modes for orexin-A into orexin 1 receptor, which help rationalize previous results from site-directed mutagenesis studies. The binding modes should serve small molecule discovery, and offer insights into the mechanism of receptor activation.

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3D-representations for the docking pose clusters and scatter plots from multidimensional scaling, NTSR1-based model. (A, C) Ten largest clusters; (B, D) Ten top-scoring clusters. The view and color coding is as in Figure 4.
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Fig5: 3D-representations for the docking pose clusters and scatter plots from multidimensional scaling, NTSR1-based model. (A, C) Ten largest clusters; (B, D) Ten top-scoring clusters. The view and color coding is as in Figure 4.

Mentions: In the OX2R-based model, the docking poses form a tight “bouquet” (Figure 4A, Additional file 6), with some poses leaning over to the TM5-side of the cavity. Top-scoring clusters occupy a tight space vertically in the middle of the binding cavity, again with some clusters leaning over to TM5 (Figure 4B). In the NTSR1-based model, the available space for the peptide ligand is fan-shaped (Figure 5A, Additional file 6), which is a result of the narrow interhelical cavity. The top-scoring clusters tend to show a vertical ligand orientation with C-terminus deep in the cavity (Figure 5B). Few clusters show poses higher and slanted towards TM1.Figure 4


Modeling of the OX1R-orexin-A complex suggests two alternative binding modes.

Karhu L, Turku A, Xhaard H - BMC Struct. Biol. (2015)

3D-representations for the docking pose clusters and scatter plots from multidimensional scaling, NTSR1-based model. (A, C) Ten largest clusters; (B, D) Ten top-scoring clusters. The view and color coding is as in Figure 4.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4469407&req=5

Fig5: 3D-representations for the docking pose clusters and scatter plots from multidimensional scaling, NTSR1-based model. (A, C) Ten largest clusters; (B, D) Ten top-scoring clusters. The view and color coding is as in Figure 4.
Mentions: In the OX2R-based model, the docking poses form a tight “bouquet” (Figure 4A, Additional file 6), with some poses leaning over to the TM5-side of the cavity. Top-scoring clusters occupy a tight space vertically in the middle of the binding cavity, again with some clusters leaning over to TM5 (Figure 4B). In the NTSR1-based model, the available space for the peptide ligand is fan-shaped (Figure 5A, Additional file 6), which is a result of the narrow interhelical cavity. The top-scoring clusters tend to show a vertical ligand orientation with C-terminus deep in the cavity (Figure 5B). Few clusters show poses higher and slanted towards TM1.Figure 4

Bottom Line: However, a better understanding of specific pairwise interactions would benefit small molecule discovery.We present two binding modes for orexin-A into orexin 1 receptor, which help rationalize previous results from site-directed mutagenesis studies.The binding modes should serve small molecule discovery, and offer insights into the mechanism of receptor activation.

View Article: PubMed Central - PubMed

Affiliation: Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, P.O. Box 56, 00014, Helsinki, Finland. lasse.karhu@helsinki.fi.

ABSTRACT

Background: Interactions between the orexin peptides and their cognate OX1 and OX2 receptors remain poorly characterized. Site-directed mutagenesis studies on orexin peptides and receptors have indicated amino acids important for ligand binding and receptor activation. However, a better understanding of specific pairwise interactions would benefit small molecule discovery.

Results: We constructed a set of three-dimensional models of the orexin 1 receptor based on the 3D-structures of the orexin 2 receptor (released while this manuscript was under review), neurotensin receptor 1 and chemokine receptor CXCR4, conducted an exhaustive docking of orexin-A16-33 peptide fragment with ZDOCK and RDOCK, and analyzed a total of 4301 complexes through multidimensional scaling and clustering. The best docking poses reveal two alternative binding modes, where the C-terminus of the peptide lies deep in the binding pocket, on average about 5-6 Å above Tyr(6.48) and close to Gln(3.32). The binding modes differ in the about 100° rotation of the peptide; the peptide His26 faces either the receptor's fifth transmembrane helix or the seventh helix. Both binding modes are well in line with previous mutation studies and partake in hydrogen bonding similar to suvorexant.

Conclusions: We present two binding modes for orexin-A into orexin 1 receptor, which help rationalize previous results from site-directed mutagenesis studies. The binding modes should serve small molecule discovery, and offer insights into the mechanism of receptor activation.

Show MeSH