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. Aj oint approach combining site-directed mutagenesis and functional assays with computational modeling has been used to explore the signaling mechanics of OR7D4. In this OR, ag enetic polymorphism affects our perception of androstenone.M olecular simulations totaling 0.12 ms predicted that, similarly to observations for other G-protein-coupled receptors with knowne xperimental structures,a na ctivation pathway connects the ligand and the G-protein binding site.T he 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 ap owerful tool to capture OR dynamics related to smell perception.Our sense of smell is triggered by the activation of odorant receptors (ORs) expressed on the surface of olfactory sensory neurons.Smelling relies on aso-called combinatorial code of OR activations. [1] Our approximately 400 ORs endow us with spectacular discriminatory power. ORs represent more than 3% of our protein-coding genes and belong to the class AGprotein-coupled receptor (GPCR) family.S tructurally, class AGPCRs are made up of seven transmembrane helices (TMs), named TM1 to TM7, which form abundle within the cell membrane.U pon activation, an allosteric signal is transmitted from the ligand to the G-protein binding site over ad istance of more than 20 (ca. 5h elix turns). [2] The intracellular part of TM6 then tilts outward with respect to its position in the inactive state. [3] Mammalian OR sequences show ah ighly conserved and OR-specific RxKAFSTCxSH motif in the intracellular part of TM6, suggesting acrucial role in the control of OR activation. In non-olfactory class AG PCRs,o nly the second lysine residue is conserved. [4] Odorant-receptor-activation dynamics still remain to be uncovered, but as ignificant body of work has focused on the molecular details of OR activation, especially concerning the interaction between ORs and ligands. [5] Thes trength of molecular-modeling approaches on GPCRs was demonstrated by ag roundbreaking study based on homology modeling and virtual screening, which deorphanized GPR68 and GPR65. [6] By applying this approach to ORs,w er ecently demonstrated how certain mutations alter receptor function or dynamics. [4,7] Human OR7D4, which is narrowly tuned to detect the testosterone metabolites androstadienone and androstenone, is as pectacular example of how natural sequence variations can affect activation and subsequent odor perception. People with two copies of the most common genetic variant (OR7D4-RTorw ild type,w t) tend to describe the androstenone smell as sickening,putrid, foul, or urine-like.However, people who possess the unresponsive R88W/T133M variant (OR7D4-WM) tend to report the smell to...