Odorant Receptor 7D4 Activation Dynamics |
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Authors: | Elise Bruguera Dr. Gleb Novikov Kentaro Ikegami Prof. Hiroaki Matsunami Prof. Jérôme Golebiowski |
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Affiliation: | 1. Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC, USA;2. Institute of Chemistry—Nice, UMR 7272 CNRS, Université C?te d'Azur, Nice cedex, France;3. Department of Biotechnology and Life Science, Tokyo University of Agriculture and Technology, Tokyo, Japan;4. Department of Neurobiology, Duke Institute for Brain Sciences, Duke University Medical Center, Durham, NC, USA;5. Department of Brain and Cognitive Sciences, DGIST, Daegu, Republic of Korea |
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Abstract: | Deciphering how an odorant activates an odorant receptor (OR) and how changes in specific OR residues affect its responsiveness are central to understanding our sense of smell. A joint approach combining site‐directed mutagenesis and functional assays with computational modeling has been used to explore the signaling mechanics of OR7D4. In this OR, a genetic polymorphism affects our perception of androstenone. Molecular simulations totaling 0.12 ms predicted that, similarly to observations for other G‐protein‐coupled receptors with known experimental structures, an activation pathway connects the ligand and the G‐protein binding site. The 3D model activation mechanism correlates with in vitro data and notably predicts that the OR7D4 WM variant is not activated. Upon activation, an OR‐specific sequence motif is the convergence point of the mechanism. Our study suggests that robust homology modeling can serve as a powerful tool to capture OR dynamics related to smell perception. |
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Keywords: | activation functional assays molecular dynamics molecular modeling olfactory receptors |
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