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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 androstenone (agonist) and undecanal (antagonist) to the human olfactory receptor 1D2.Both the odorants bind in the same binding pocket but interact with different residues. Val108, Val 109, Phe 168, Ile 187, Ser 230, Tyr 233 and Gly 234 are the common residues at the binding site. 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.g011: Binding mode of androstenone (agonist) and undecanal (antagonist) to the human olfactory receptor 1D2.Both the odorants bind in the same binding pocket but interact with different residues. Val108, Val 109, Phe 168, Ile 187, Ser 230, Tyr 233 and Gly 234 are the common residues at the binding site. 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: Undecanal is a known inhibitor for human olfactory receptor hOr17-4 (1D2) (Table 9) [59] [61] and for its homologue in rat, the I7 receptor. The human and the rat ORs are known to respond to bourgeonal, the agonist [15]. The gscore of undecanal interaction with the receptor 1D2 in this study is -5.2 kcal/mol, which is lower than binding affinity of the highest scoring pair (-10.73kcal/mol), but better than bourgeonal (-4.48Kcal/mol) which is the known agonist (inhibited by undecanal). The binding site of undecanal is same as the other high scoring ligands, suggesting competitive inhibition of these receptors by undecanal (Fig 11).


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

Harini K, Sowdhamini R - PLoS ONE (2015)

Binding mode of androstenone (agonist) and undecanal (antagonist) to the human olfactory receptor 1D2.Both the odorants bind in the same binding pocket but interact with different residues. Val108, Val 109, Phe 168, Ile 187, Ser 230, Tyr 233 and Gly 234 are the common residues at the binding site. 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.g011: Binding mode of androstenone (agonist) and undecanal (antagonist) to the human olfactory receptor 1D2.Both the odorants bind in the same binding pocket but interact with different residues. Val108, Val 109, Phe 168, Ile 187, Ser 230, Tyr 233 and Gly 234 are the common residues at the binding site. 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: Undecanal is a known inhibitor for human olfactory receptor hOr17-4 (1D2) (Table 9) [59] [61] and for its homologue in rat, the I7 receptor. The human and the rat ORs are known to respond to bourgeonal, the agonist [15]. The gscore of undecanal interaction with the receptor 1D2 in this study is -5.2 kcal/mol, which is lower than binding affinity of the highest scoring pair (-10.73kcal/mol), but better than bourgeonal (-4.48Kcal/mol) which is the known agonist (inhibited by undecanal). The binding site of undecanal is same as the other high scoring ligands, suggesting competitive inhibition of these receptors by undecanal (Fig 11).

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.