The Importance of Odorant Conformation to the Binding and Activation of a Representative Olfactory Receptor

Peterlin, Zita; Li, Yadi; Sun, Guangyuan; Shah, Rohan; Firestein, Stuart; Ryan, Kevin

doi:10.1016/j.chembiol.2008.10.014

Cited by 57 publications

(111 citation statements)

References 33 publications

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“…One possibility is that these odorants do so by receptor antagonism in the nose. This mechanism would be consistent with previous reports of odorants that can act as antagonists to block the activation of certain ORs or nasal neurons by other odorants (37)(38)(39).…”

Section: Resultssupporting

confidence: 80%

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Combinatorial effects of odorants on mouse behavior

Saraiva

Kondoh

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

130

160

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The mechanisms by which odors induce instinctive behaviors are largely unknown. Odor detection in the mouse nose is mediated by >1, 000 different odorant receptors (ORs) and trace amine-associated receptors (TAARs). Odor perceptions are encoded combinatorially by ORs and can be altered by slight changes in the combination of activated receptors. However, the stereotyped nature of instinctive odor responses suggests the involvement of specific receptors and genetically programmed neural circuits relatively immune to extraneous odor stimuli and receptor inputs. Here, we report that, contrary to expectation, innate odor-induced behaviors can be context-dependent. First, different ligands for a given TAAR can vary in behavioral effect. Second, when combined, some attractive and aversive odorants neutralize one another's behavioral effects. Both a TAAR ligand and a common odorant block aversion to a predator odor, indicating that this ability is not unique to TAARs and can extend to an aversive response of potential importance to survival. In vitro testing of single receptors with binary odorant mixtures indicates that behavioral blocking can occur without receptor antagonism in the nose. Moreover, genetic ablation of a single receptor prevents its cognate ligand from blocking predator odor aversion, indicating that the blocking requires sensory input from the receptor. Together, these findings indicate that innate odor-induced behaviors can depend on context, that signals from a single receptor can block innate odor aversion, and that instinctive behavioral responses to odors can be modulated by interactions in the brain among signals derived from different receptors.olfaction | behavior | TAAR | odorants

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Section: Resultssupporting

confidence: 80%

“…Previous studies indicate that odorants can act not only as agonists but also antagonists for ORs (37)(38)(39). Single odorants have been shown to block activation of a specific OR or nasal neurons by another odorant.…”

Section: Innate Odor Responses Can Be Modulated By Combinatorial Odorantmentioning

confidence: 99%

Combinatorial effects of odorants on mouse behavior

Saraiva

Kondoh

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

130

160

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“…Several efforts to determine the ligand specificity of ORs have revealed that each individual OR not only demonstrates a high specificity for some functional groups and molecular features, but also has high tolerance in some aspects [43,46,[48][49][50][51][52][53][54][55][56]. That is, ORs appear to discriminate between and recognize a wide variety of structurally similar odorants.…”

Section: Olfactory Receptor Pharmacologymentioning

confidence: 99%

Mammalian olfactory receptors: pharmacology, G protein coupling and desensitization

Kato

Touhara

2009

Cell. Mol. Life Sci.

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The vertebrate olfactory system recognizes and discriminates between thousands of structurally diverse odorants. Detection of odorants in mammals is mediated by olfactory receptors (ORs), which comprise the largest superfamily of G protein-coupled receptors (GPCRs). Upon odorant binding, ORs couple to G proteins, resulting in an increase in intracellular cAMP levels and subsequent receptor signaling. In this review, we will discuss recently published studies outlining the molecular basis of odor discrimination, focusing on pharmacology, G protein activation, and desensitization of ORs. A greater understanding of the molecular mechanisms underlying OR activity may help in the discovery of agonists and antagonists of ORs, and of GPCRs with potential therapeutic applications.

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“…A dynamic binding mode with fluctuating hydrogen bonds between receptor and ligand offers a solution to cope with the high flexibility of the odorant ligand. [47] . Thus, we investigated the hydrogen bond contact frequencies between amylbutyrate and Ser263 6.51 , Ser264 6.52 , and Thr279 7.42 , by classifying hydrogen bonds as robust (present in 100-50 % of the simulated time), fluctuating (49-25 %), and temporary (24-1 %).…”

mentioning

confidence: 95%

Prediction of a Ligand‐Binding Niche within a Human Olfactory Receptor by Combining Site‐Directed Mutagenesis with Dynamic Homology Modeling

et al. 2011

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The mammalian olfactory system comprises a large family of G protein-coupled receptors (GPCRs) to detect and discriminate numerous volatile ligands. More than 350 human genes encode functional olfactory receptors (ORs) [1] that belong to the class A (rhodopsin-like) GPCR family. [2] Owing to difficulties with functional OR expression in heterologous systems, [3,4] only a few human ORs have been characterized to date. Most deorphanized ORs, that is, ORs with a known ligand spectrum, detect multiple chemically similar odorants, [5] and hypervariable residues in the seven transmembrane (7TM) helices (I-VII) have been postulated to form the basis for ligand specificity.[6] A prerequisite for understanding olfactory receptor selectivity is information on the spatial properties of the ligand-binding niche. Different classes of approaches have been employed for such an assessment: [7] Ligand-based approaches, such as pharmacophore modeling or quantitative structure-activity relationship (QSAR), can give valuable models of the ligand structure, which is required for discriminating activating and inactive ligands, and information on the form of the binding pocket. [8][9][10][11] Receptor-based approaches such as homology modeling create a model of the protein and the binding site explicitly, [12][13][14][15][16][17][18] and from this give information on ligand binding. Both techniques can be combined together. [19][20][21][22] For such receptor-based and mixed approaches, the X-ray structures of seven GPCRs have been solved to date, [23][24][25][26][27][28][29][30][31][32] but none for ORs. Previous studies have used static structural models of different ORs based on a rhodopsin [12][13][14][15][16][17][18][19][20][21] and a b 2 -adrenergic receptor (B2AR) [33] template. However, most odorants are highly flexible, so assessment of the ligand/protein dynamics might be of crucial importance in understanding ligand recognition by ORs. To better understand receptor activation, we thus searched for a dynamic ligand-protein interaction pattern instead of analyzing ligand-binding in static models. Therefore, in difference to other flexible GPCR ligand pocket analysis approaches, [34][35][36][37] we use the predictive power of protein/ligand complex molecular dynamics (MD) simulations [38][39][40] to gain insight into the protein-odorant dynamics necessary for receptor activation.We developed a dynamic model of the functionally wellcharacterized human olfactory receptor hOR2AG1.[41] We used an X-ray structure of bovine rhodopsin with 2.2 resolution [24] as starting structure for dynamic homology modeling of hOR2AG1, since both receptors belong to the class A GPCRs, and both harbor hydrophobic ligands. The performance of this approach was previously tested by homology modeling of the B2AR ligand-binding niche based on the rhodopsin template (see Supporting Information, Section 1 a).[40] Although the overall sequence identity among class A GPCRs is relatively low, this can be compensated for by careful incorporation of experimental...

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The Importance of Odorant Conformation to the Binding and Activation of a Representative Olfactory Receptor

Cited by 57 publications

References 33 publications

Combinatorial effects of odorants on mouse behavior

Combinatorial effects of odorants on mouse behavior

Mammalian olfactory receptors: pharmacology, G protein coupling and desensitization

Prediction of a Ligand‐Binding Niche within a Human Olfactory Receptor by Combining Site‐Directed Mutagenesis with Dynamic Homology Modeling

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