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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 Helional and (-) Citronellol to human OR1A1.Helional (a) forms three hydrogen bonds and one salt bridge with the residues of OR1A1, while Citronellol (b) forms only one H-bond with the residues of OR. Helional is known to be the most potent alcohol for human ORs. 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.g009: Binding mode of Helional and (-) Citronellol to human OR1A1.Helional (a) forms three hydrogen bonds and one salt bridge with the residues of OR1A1, while Citronellol (b) forms only one H-bond with the residues of OR. Helional is known to be the most potent alcohol for human ORs. 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 OR1A1 (belonging to OR pair 2) responds to citronellol and helional even at lower concentrations when compared to aldehydes with 6–9 carbons atoms (Table 9) [58]. Among the different stereoisomers of citronellol, the receptor is more responsive to (-) citronellol than (+) citronellol. The hydrophobic binding pocket is very similar to the one observed in mOR-EG receptor. The TM 3, 4, 5, 6, and 7 are involved in interactions with the ligand. Gly 108, Asn 109 and Ser 112 are involved in interactions with the ligand and mutation of these residues results in a reduction of response to these odorants. These residues are found in the binding pocket of OR1A1, derived from the current OR-ligand docking protocol. Helional is the highest scoring ligand (-8.51kcal/mol) in this mini-virtual screening exercise, while (-) citronellol obtains a GLIDE score of -5.76kcal/mol, though the binding pockets for both ligands are similar in our analysis (Fig 9). (+) citronellol scores lower than the two above mentioned odorants. Comparing the residues at the binding pocket for the close homologue of OR1A1 in mouse (Fig 5), we observe that the four residues known to be important in ligand binding are common, while the rest of the binding pockets differ in the composition of residues. This variability at the functional site allows the closely related OR sequences to bind to myriad odorants.


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

Harini K, Sowdhamini R - PLoS ONE (2015)

Binding mode of Helional and (-) Citronellol to human OR1A1.Helional (a) forms three hydrogen bonds and one salt bridge with the residues of OR1A1, while Citronellol (b) forms only one H-bond with the residues of OR. Helional is known to be the most potent alcohol for human ORs. 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

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getmorefigures.php?uid=PMC4519343&req=5

pone.0131077.g009: Binding mode of Helional and (-) Citronellol to human OR1A1.Helional (a) forms three hydrogen bonds and one salt bridge with the residues of OR1A1, while Citronellol (b) forms only one H-bond with the residues of OR. Helional is known to be the most potent alcohol for human ORs. 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 OR1A1 (belonging to OR pair 2) responds to citronellol and helional even at lower concentrations when compared to aldehydes with 6–9 carbons atoms (Table 9) [58]. Among the different stereoisomers of citronellol, the receptor is more responsive to (-) citronellol than (+) citronellol. The hydrophobic binding pocket is very similar to the one observed in mOR-EG receptor. The TM 3, 4, 5, 6, and 7 are involved in interactions with the ligand. Gly 108, Asn 109 and Ser 112 are involved in interactions with the ligand and mutation of these residues results in a reduction of response to these odorants. These residues are found in the binding pocket of OR1A1, derived from the current OR-ligand docking protocol. Helional is the highest scoring ligand (-8.51kcal/mol) in this mini-virtual screening exercise, while (-) citronellol obtains a GLIDE score of -5.76kcal/mol, though the binding pockets for both ligands are similar in our analysis (Fig 9). (+) citronellol scores lower than the two above mentioned odorants. Comparing the residues at the binding pocket for the close homologue of OR1A1 in mouse (Fig 5), we observe that the four residues known to be important in ligand binding are common, while the rest of the binding pockets differ in the composition of residues. This variability at the functional site allows the closely related OR sequences to bind to myriad odorants.

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.