Structural basis of odorant recognition by a human odorant receptor

Machine Learning-Based Modeling of Olfactory Receptors in Their Inactive State: Human OR51E2 as a Case Study

“…In the AF/OF model, R262 6.59 points toward the membrane, while S258 6.55 is involved in an intrahelical H-bond with L254 6.54 . Instead, in the AF in model, both residues are pointing inside the binding cavity; thus, this model is more compatible with these two residues forming hydrogen bonds with the propionate ligand in the cryo-EM structure …”

“…Lastly, we compared the TM6–TM7 interfaces obtained for our two best in silico models (AF in and AF/OF) with the one observed in the only experimental structure of hOR51E2 available as of April 2023 (PDB 8F76). Taking into account that a direct comparison is not straightforward due to their different conformational state (the experimental structure corresponds to a receptor in its active state, whereas our models are in the inactive state), we can observe that the TM6–TM7 interhelical contacts are almost identical to the ones observed with AF in (see Figure ). Namely, the TM6 residues commonly identified as part of the interface for both the AF in and experimental structures are S242 6.39 , V246 6.43 , and F250 6.47 .…”

“…To verify the reliability of an out-of-the-box in silico approach to predict OR structures and dynamics, we tested a set of models generated with six different predictors, followed by submicrosecond molecular dynamics (MD) simulations. We chose to focus on the human olfactory receptor 51E2 (hOR51E2), associated with prostate cancer, because it has been widely studied, both experimentally and computationally. , Based on our test case, we propose a protocol to build reliable models of inactive, sodium-bound OR structures.…”

“…Afterward, we observe a bending in the TM6–TM7 relative orientation (most likely related with the active state of the receptor in the cryo-EM structure); as a result P235 6.50 becomes the last main actor of the hydrophobic interface, similarly to the AF/OF models (which are trained on both active and inactive GPCR conformations, unlike the state-specific AF in ). A further indication that the TM6 structure is key for understanding the structure–function relationships of hOR51E2 can be found in the side chain orientation of the two TM6 residues (i.e., S258 6.55 and R262 6.59 ) involved in ligand binding based on the cryo-EM structure and mutagenesis data . In the AF/OF model, R262 6.59 points toward the membrane, while S258 6.55 is involved in an intrahelical H-bond with L254 6.54 .…”

Introduction to volatile natural products

“…There are about 400 functional human odorant receptors 1 allowing the discrimination of a vast array of structurally diverse volatiles by activating a specific subset of different receptors. 2 The apparent capacity of volatiles to induce emotional reactions in humans shows the high importance of the olfactory sense, even to us. This importance of volatiles is heightened in many other animals, i.e.…”