A computational microscope focused on the sense of smell

March, Claire A. de; Golebiowski, Jérôme

doi:10.1016/j.biochi.2014.06.006

Cited by 16 publications

(14 citation statements)

References 136 publications

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“…7a, 14 Most amino acid residues we identified as belonging to the binding site (made up of residues from the upper parts towards the extracellular side) of the helices of TM3, TM5, TM6 and TM7) are consistent with previous studies (ref. 15 and references therein).…”

Section: Resultssupporting

confidence: 90%

Conserved Residues Control Activation of Mammalian G Protein-Coupled Odorant Receptors

March

et al. 2015

J. Am. Chem. Soc.

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102

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Odorant Receptor (OR) genes and proteins represent more than 2% of our genome and 4% of our proteome 25 and constitute the largest sub-group of G Protein-Coupled Receptors (GPCRs). The mechanism underlying OR activation remains poorly understood, as they do not share some of the highly conserved motifs critical for activation of non-olfactory GPCRs. By combining site-directed mutagenesis, heterologous expression, and molecular dynamics simulations that capture the conformational change of constitutively active mutants, we tentatively identified crucial residues for the function of these receptors using the mouse MOR256-3 (Olfr124) as a model. The toggle-switch for sensing agonists in-volves a highly conserved tyrosine residue in helix VI. The ionic-lock is located between the `DRY' motif in helix III and a positively charged `R/K' residue in helix VI. This study provides an unprecedented model that captures the main mechanisms of odorant receptor activation.

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Section: Resultssupporting

confidence: 90%

Conserved Residues Control Activation of Mammalian G Protein-Coupled Odorant Receptors

March

et al. 2015

J. Am. Chem. Soc.

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102

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“…Only recently have in silico approaches been used for the purpose of OR deorphanization. A detailed review of modelling approaches has been published recently . As with all techniques, a trade‐off between speed and accuracy must be made.…”

Section: Interactions Between Ors and Odourantsmentioning

confidence: 99%

“…A detailed review of modelling approaches has been published recently. [110] As with all techniques, a trade-off between speed and accuracy must be made. By using a rapid screening based on docking (which was already used for the purpose of mORs deorphanization) [111] on a large database of more than 500 odourants, researchers were able to predict 40 potential mOR42-3 agonists of which half were experimentally assessed.…”

Section: Computational Approachesmentioning

confidence: 99%

Structure–odour relationships reviewed in the postgenomic era

March

Ryu

Sicard

et al. 2015

Flavour & Fragrance J

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This review reports on the knowledge about odourant–olfactory receptor interactions and their projection within the field of structure–odour relationships (SOR). We provide a list of agonists and odour spaces associated with deorphanized human olfactory receptors. The link between olfactory receptor responses, differential perception and subtleties within odour families is discussed. Copyright © 2015 John Wiley & Sons, Ltd.

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“…In addition, experimental data [8] is available to validate the predictions for several mutants and the functional response to various odorant molecules. Recently homology modeling and limited applications of our methods have been applied to hOR1G1 to identify the residues controlling odorant recognition [1,7].…”

Section: Introductionmentioning

confidence: 99%

“…The human olfactory system involves *396 olfactory receptors (ORs) that are responsible for mediating the sense of smell [1]. These ORs provide a unique connection between fundamental signaling at the molecular level and macroscale issues of perception.…”

Section: Introductionmentioning

confidence: 99%

Predicted 3D structures of olfactory receptors with details of odorant binding to OR1G1

Kim

Goddard

2014

J Comput Aided Mol Des

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Olfactory receptors (ORs) are responsible for mediating the sense of smell; they allow humans to recognize an enormous number of odors but the connection between binding and perception is not known. We predict the ensemble of low energy structures for the human OR1G1 (hOR1G1) and also for six other diverse ORs, using the G protein-coupled receptor Ensemble of Structures in Membrane BiLayer Environment complete sampling method that samples 13 trillion different rotations and tilts using four different templates to predict the 24 structures likely to be important in binding and activation. Our predicted most stable structures of hOR1G1 have a salt-bridge between the conserved D3.49 and K6.30 in the D(E)RY region, that we expect to be associated with an inactive form. The hOR1G1 structure also has specific interaction in transmembrane domains (TMD) 3-6 (E3.39 and H6.40), which is likely an important conformational feature for all hORs because of the ~94 to 98 % conservation among all hOR sequences. Of the five ligands studied (nonanal, 9-decen-1-ol, 1-nonanol, camphor, and n-butanal), we find that the 4 expected to bind lead to similar binding energies with nonanol the strongest.

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A computational microscope focused on the sense of smell

Cited by 16 publications

References 136 publications

Conserved Residues Control Activation of Mammalian G Protein-Coupled Odorant Receptors

Conserved Residues Control Activation of Mammalian G Protein-Coupled Odorant Receptors

Structure–odour relationships reviewed in the postgenomic era

Predicted 3D structures of olfactory receptors with details of odorant binding to OR1G1

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