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Computational Approaches for Decoding Select Odorant-Olfactory Receptor Interactions Using Mini-Virtual Screening.

Harini K, Sowdhamini R - PLoS ONE (2015)

Bottom Line: Ligand docking results were applied on homologous pairs (with varying sequence identity) of ORs from human and mouse genomes and ligand binding residues and the ligand profile differed among such related olfactory receptor sequences.This study revealed that homologous sequences with high sequence identity need not bind to the same/ similar ligand with a given affinity.A ligand profile has been obtained for each of the 20 receptors in this analysis which will be useful for expression and mutation studies on these receptors.

View Article: PubMed Central - PubMed

Affiliation: National Centre for Biological Sciences (TIFR), GKVK Campus, Bellary Road, Bangalore, India.

ABSTRACT
Olfactory receptors (ORs) belong to the class A G-Protein Coupled Receptor superfamily of proteins. Unlike G-Protein Coupled Receptors, ORs exhibit a combinatorial response to odors/ligands. ORs display an affinity towards a range of odor molecules rather than binding to a specific set of ligands and conversely a single odorant molecule may bind to a number of olfactory receptors with varying affinities. The diversity in odor recognition is linked to the highly variable transmembrane domains of these receptors. The purpose of this study is to decode the odor-olfactory receptor interactions using in silico docking studies. In this study, a ligand (odor molecules) dataset of 125 molecules was used to carry out in silico docking using the GLIDE docking tool (SCHRODINGER Inc Pvt LTD). Previous studies, with smaller datasets of ligands, have shown that orthologous olfactory receptors respond to similarly-tuned ligands, but are dramatically different in their efficacy and potency. Ligand docking results were applied on homologous pairs (with varying sequence identity) of ORs from human and mouse genomes and ligand binding residues and the ligand profile differed among such related olfactory receptor sequences. This study revealed that homologous sequences with high sequence identity need not bind to the same/ similar ligand with a given affinity. A ligand profile has been obtained for each of the 20 receptors in this analysis which will be useful for expression and mutation studies on these receptors.

No MeSH data available.


Binding mode of bourgeonal to human OR1D2.Bourgeonal is known to be the most potent ligand of human OR1D2. It forms a H-bond with the residue Phe168 of the receptor. It binds to the common GPCR binding pocket formed by TM3, 4, 5 and 7. The figure is obtained using the “Ligand Interaction Diagram” of the GLIDE software (Schrödinger Release 2013–1:, version 2.6, Schrödinger, LLC, New York, NY, 2013).
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pone.0131077.g010: Binding mode of bourgeonal to human OR1D2.Bourgeonal is known to be the most potent ligand of human OR1D2. It forms a H-bond with the residue Phe168 of the receptor. It binds to the common GPCR binding pocket formed by TM3, 4, 5 and 7. The figure is obtained using the “Ligand Interaction Diagram” of the GLIDE software (Schrödinger Release 2013–1:, version 2.6, Schrödinger, LLC, New York, NY, 2013).

Mentions: Human OR1D2 is a receptor found in human spermatozoa [59]. It is known to respond to bourgeonal and is suppressed by undecanal (Table 9). The OR1D2 receptor is evolutionarily related to the human receptor 7D4, that detects steroids such as androstenone and androstadienone. Point mutations in OR7D4 result in variations in response to the known odorants across different individuals [60]. It is reported that OR1D2 also responds to steroid hormones with lesser efficacy as compared to OR7D4 (Table 9). In the docking analysis, androstenone and androstadienone are observed as the best scoring ligands for 1D2, with a GLIDE score in the range of -10kcal/mol, while bourgeonal binds with a score of -4.48kcal/mol. The binding pockets remain similar for both the odorants. This study confirms the fact that by subtle changes at the receptor binding site, the receptor can accommodate similar ligands. The difference in ligand binding scores could be because of the difference in the functional groups of the odorants (Fig 10).


Computational Approaches for Decoding Select Odorant-Olfactory Receptor Interactions Using Mini-Virtual Screening.

Harini K, Sowdhamini R - PLoS ONE (2015)

Binding mode of bourgeonal to human OR1D2.Bourgeonal is known to be the most potent ligand of human OR1D2. It forms a H-bond with the residue Phe168 of the receptor. It binds to the common GPCR binding pocket formed by TM3, 4, 5 and 7. The figure is obtained using the “Ligand Interaction Diagram” of the GLIDE software (Schrödinger Release 2013–1:, version 2.6, Schrödinger, LLC, New York, NY, 2013).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4519343&req=5

pone.0131077.g010: Binding mode of bourgeonal to human OR1D2.Bourgeonal is known to be the most potent ligand of human OR1D2. It forms a H-bond with the residue Phe168 of the receptor. It binds to the common GPCR binding pocket formed by TM3, 4, 5 and 7. The figure is obtained using the “Ligand Interaction Diagram” of the GLIDE software (Schrödinger Release 2013–1:, version 2.6, Schrödinger, LLC, New York, NY, 2013).
Mentions: Human OR1D2 is a receptor found in human spermatozoa [59]. It is known to respond to bourgeonal and is suppressed by undecanal (Table 9). The OR1D2 receptor is evolutionarily related to the human receptor 7D4, that detects steroids such as androstenone and androstadienone. Point mutations in OR7D4 result in variations in response to the known odorants across different individuals [60]. It is reported that OR1D2 also responds to steroid hormones with lesser efficacy as compared to OR7D4 (Table 9). In the docking analysis, androstenone and androstadienone are observed as the best scoring ligands for 1D2, with a GLIDE score in the range of -10kcal/mol, while bourgeonal binds with a score of -4.48kcal/mol. The binding pockets remain similar for both the odorants. This study confirms the fact that by subtle changes at the receptor binding site, the receptor can accommodate similar ligands. The difference in ligand binding scores could be because of the difference in the functional groups of the odorants (Fig 10).

Bottom Line: Ligand docking results were applied on homologous pairs (with varying sequence identity) of ORs from human and mouse genomes and ligand binding residues and the ligand profile differed among such related olfactory receptor sequences.This study revealed that homologous sequences with high sequence identity need not bind to the same/ similar ligand with a given affinity.A ligand profile has been obtained for each of the 20 receptors in this analysis which will be useful for expression and mutation studies on these receptors.

View Article: PubMed Central - PubMed

Affiliation: National Centre for Biological Sciences (TIFR), GKVK Campus, Bellary Road, Bangalore, India.

ABSTRACT
Olfactory receptors (ORs) belong to the class A G-Protein Coupled Receptor superfamily of proteins. Unlike G-Protein Coupled Receptors, ORs exhibit a combinatorial response to odors/ligands. ORs display an affinity towards a range of odor molecules rather than binding to a specific set of ligands and conversely a single odorant molecule may bind to a number of olfactory receptors with varying affinities. The diversity in odor recognition is linked to the highly variable transmembrane domains of these receptors. The purpose of this study is to decode the odor-olfactory receptor interactions using in silico docking studies. In this study, a ligand (odor molecules) dataset of 125 molecules was used to carry out in silico docking using the GLIDE docking tool (SCHRODINGER Inc Pvt LTD). Previous studies, with smaller datasets of ligands, have shown that orthologous olfactory receptors respond to similarly-tuned ligands, but are dramatically different in their efficacy and potency. Ligand docking results were applied on homologous pairs (with varying sequence identity) of ORs from human and mouse genomes and ligand binding residues and the ligand profile differed among such related olfactory receptor sequences. This study revealed that homologous sequences with high sequence identity need not bind to the same/ similar ligand with a given affinity. A ligand profile has been obtained for each of the 20 receptors in this analysis which will be useful for expression and mutation studies on these receptors.

No MeSH data available.