scholarly journals G protein-coupled odorant receptors: From sequence to structure

2015 ◽  
Vol 24 (9) ◽  
pp. 1543-1548 ◽  
Author(s):  
Claire A. de March ◽  
Soo-Kyung Kim ◽  
Serge Antonczak ◽  
William A. Goddard ◽  
Jérôme Golebiowski
Keyword(s):  
G Protein ◽  
Odorant Receptors ◽  
G Protein Coupled

scholarly journals G protein-coupled odorant receptors underlie mechanosensitivity in mammalian olfactory sensory neurons

2014 ◽  
Vol 112 (2) ◽  
pp. 590-595 ◽  
Author(s):  
Timothy Connelly ◽  
Yiqun Yu ◽  
Xavier Grosmaitre ◽  
Jue Wang ◽  
Lindsey C. Santarelli ◽  
...  
Keyword(s):  
G Protein ◽  
Sensory Neurons ◽  
Ectopic Expression ◽  
Host Cells ◽  
Odorant Receptors ◽  
Olfactory Sensory Neurons ◽  
Mechanical Stimuli ◽  
Genetic Ablation ◽  
Mechanical Responses ◽  
G Protein Coupled

Mechanosensitive cells are essential for organisms to sense the external and internal environments, and a variety of molecules have been implicated as mechanical sensors. Here we report that odorant receptors (ORs), a large family of G protein-coupled receptors, underlie the responses to both chemical and mechanical stimuli in mouse olfactory sensory neurons (OSNs). Genetic ablation of key signaling proteins in odor transduction or disruption of OR–G protein coupling eliminates mechanical responses. Curiously, OSNs expressing different OR types display significantly different responses to mechanical stimuli. Genetic swap of putatively mechanosensitive ORs abolishes or reduces mechanical responses of OSNs. Furthermore, ectopic expression of an OR restores mechanosensitivity in loss-of-function OSNs. Lastly, heterologous expression of an OR confers mechanosensitivity to its host cells. These results indicate that certain ORs are both necessary and sufficient to cause mechanical responses, revealing a previously unidentified mechanism for mechanotransduction.

scholarly journals Beyond the Flavour: The Potential Druggability of Chemosensory G Protein-Coupled Receptors

2019 ◽  
Vol 20 (6) ◽  
pp. 1402 ◽  
Author(s):  
Antonella Di Pizio ◽  
Maik Behrens ◽  
Dietmar Krautwurst
Keyword(s):  
G Protein ◽  
Drug Targets ◽  
Current Knowledge ◽  
Chemical Space ◽  
G Protein Coupled Receptors ◽  
The Body ◽  
Odorant Receptors ◽  
Taste Receptors ◽  
Umami Taste ◽  
G Protein Coupled

G protein-coupled receptors (GPCRs) belong to the largest class of drug targets. Approximately half of the members of the human GPCR superfamily are chemosensory receptors, including odorant receptors (ORs), trace amine-associated receptors (TAARs), bitter taste receptors (TAS2Rs), sweet and umami taste receptors (TAS1Rs). Interestingly, these chemosensory GPCRs (csGPCRs) are expressed in several tissues of the body where they are supposed to play a role in biological functions other than chemosensation. Despite their abundance and physiological/pathological relevance, the druggability of csGPCRs has been suggested but not fully characterized. Here, we aim to explore the potential of targeting csGPCRs to treat diseases by reviewing the current knowledge of csGPCRs expressed throughout the body and by analysing the chemical space and the drug-likeness of flavour molecules.

scholarly journals Structural instability and divergence from conserved residues underlie intracellular retention of mammalian odorant receptors

2020 ◽  
Vol 117 (6) ◽  
pp. 2957-2967
Author(s):  
Kentaro Ikegami ◽  
Claire A. de March ◽  
Maira H. Nagai ◽  
Soumadwip Ghosh ◽  
Matthew Do ◽  
...  
Keyword(s):  
Cell Surface ◽  
G Protein ◽  
Surface Expression ◽  
Structural Instability ◽  
G Protein Coupled Receptors ◽  
Machine Learning Techniques ◽  
Odorant Receptors ◽  
Cell Surface Expression ◽  
Conserved Residues ◽  
G Protein Coupled

Mammalian odorant receptors are a diverse and rapidly evolving set of G protein-coupled receptors expressed in olfactory cilia membranes. Most odorant receptors show little to no cell surface expression in nonolfactory cells due to endoplasmic reticulum retention, which has slowed down biochemical studies. Here we provide evidence that structural instability and divergence from conserved residues of individual odorant receptors underlie intracellular retention using a combination of large-scale screening of odorant receptors cell surface expression in heterologous cells, point mutations, structural modeling, and machine learning techniques. We demonstrate the importance of conserved residues by synthesizing consensus odorant receptors that show high levels of cell surface expression similar to conventional G protein-coupled receptors. Furthermore, we associate in silico structural instability with poor cell surface expression using molecular dynamics simulations. We propose an enhanced evolutionary capacitance of olfactory sensory neurons that enable the functional expression of odorant receptors with cryptic mutations.

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

2015 ◽  
Vol 137 (26) ◽  
pp. 8611-8616 ◽  
Author(s):  
Claire A. de March ◽  
Yiqun Yu ◽  
Mengjue J. Ni ◽  
Kaylin A. Adipietro ◽  
Hiroaki Matsunami ◽  
...  
Keyword(s):  
G Protein ◽  
Odorant Receptors ◽  
Conserved Residues ◽  
G Protein Coupled ◽  
Control Activation

scholarly journals Agonists of G-Protein-Coupled Odorant Receptors Are Predicted from Chemical Features

2018 ◽  
Vol 9 (9) ◽  
pp. 2235-2240 ◽  
Author(s):  
C. Bushdid ◽  
C. A. de March ◽  
S. Fiorucci ◽  
H. Matsunami ◽  
J. Golebiowski
Keyword(s):  
G Protein ◽  
Odorant Receptors ◽  
G Protein Coupled

scholarly journals Structural instability and divergence from conserved residues underlie intracellular retention of mammalian odorant receptors

2019 ◽  
Author(s):  
Kentaro Ikegami ◽  
Claire A. de March ◽  
Maira H. Nagai ◽  
Soumadwip Ghosh ◽  
Matthew Do ◽  
...  
Keyword(s):  
Cell Surface ◽  
G Protein ◽  
Surface Expression ◽  
Structural Instability ◽  
G Protein Coupled Receptors ◽  
Odorant Receptors ◽  
Cell Surface Expression ◽  
Conserved Residues ◽  
Olfactory Cells ◽  
G Protein Coupled

AbstractMammalian odorant receptors are a diverse and rapidly evolving set of G protein-coupled receptors expressed in olfactory cilia membranes. Most odorant receptors show little to no cell surface expression in non-olfactory cells due to endoplasmic reticulum retention, which has slowed down biochemical studies. Here, we provide evidence that structural instability and divergence from conserved residues of individual odorant receptors underlie intracellular retention using a combination of large-scale screening of odorant receptors cell surface expression in heterologous cells, point mutations, structural modeling, and machine learning techniques. We demonstrate the importance of conserved residues by synthesizing “consensus” odorant receptors that show high levels of cell surface expression similar to conventional G protein-coupled receptors. Furthermore, we associate in silico structural instability with poor cell surface expression using molecular dynamics simulations. We propose an enhanced evolutionary capacitance of olfactory sensory neurons that enable the functional expression of odorant receptors with cryptic mutations.Significance StatementOdor detection in mammals depends on the largest family of G protein-coupled receptors, the odorant receptors, which represent ∼2% of our protein-coding genes. The vast majority of odorant receptors are trapped within the cell when expressed in non-olfactory cells. The underlying causes of why odorant receptors cannot be functionally expressed in non-olfactory cells have remained enigmatic for over 20 years. Our study points to divergence from a consensus sequence as a key factor in a receptor’s inability to function in non-olfactory cells, which in turn, helps explain odorant receptors’ exceptional functional diversity and rapid evolution. We also show the success of protein engineering strategies for promoting odorant receptor cell surface expression.

scholarly journals Responsiveness of G protein-coupled odorant receptors is partially attributed to the activation mechanism

2015 ◽  
Vol 112 (48) ◽  
pp. 14966-14971 ◽  
Author(s):  
Yiqun Yu ◽  
Claire A. de March ◽  
Mengjue J. Ni ◽  
Kaylin A. Adipietro ◽  
Jérôme Golebiowski ◽  
...  
Keyword(s):  
G Protein ◽  
Receptor Activation ◽  
Site Directed Mutagenesis ◽  
Activation Mechanism ◽  
Odorant Receptors ◽  
Structural Basis ◽  
Single Mutation ◽  
Response Properties ◽  
Basal Activity ◽  
G Protein Coupled

Mammals detect and discriminate numerous odors via a large family of G protein-coupled odorant receptors (ORs). However, little is known about the molecular and structural basis underlying OR response properties. Using site-directed mutagenesis and computational modeling, we studied ORs sharing high sequence homology but with different response properties. When tested in heterologous cells by diverse odorants, MOR256-3 responded broadly to many odorants, whereas MOR256-8 responded weakly to a few odorants. Out of 36 mutant MOR256-3 ORs, the majority altered the responses to different odorants in a similar manner and the overall response of an OR was positively correlated with its basal activity, an indication of ligand-independent receptor activation. Strikingly, a single mutation in MOR256-8 was sufficient to confer both high basal activity and broad responsiveness to this receptor. These results suggest that broad responsiveness of an OR is at least partially attributed to its activation likelihood.

Odorant receptors: a plethora of G-protein-coupled receptors

1999 ◽  
Vol 20 (10) ◽  
pp. 413-417 ◽  
Author(s):  
Laurence Dryer ◽  
Anna Berghard
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptors ◽  
Odorant Receptors ◽  
G Protein Coupled
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