Structural highlights
Publication Abstract from PubMedOlfactory receptors (ORs) are a diverse superfamily of G protein-coupled receptors responsible for odor detection that are also implicated in non-olfactory physiological functions. OR6A2, a class II OR, selectively senses medium-chain aldehydes and belongs to a cluster of ORs genetically associated with the "soapy" perception of cilantro. It also modulates macrophage-mediated inflammatory responses. Structural studies of ORs have long been challenging. Using a back-mutation strategy, we engineered a functional OR6A2 variant (bmOR6A2) from a consensus OR6 (consOR6). Structures of bmOR6A2 in complex with aldehydes reveal a novel ligand-recognition mechanism involving a reversible Schiff base linkage with residue K(4.60), validated by mass spectrometry. By integrating structures of consOR6, molecular dynamics simulations, and functional assays, we identified a conserved D(45.51)Y(6.55)Y(7.41) triad critical for activation in class II ORs. These findings establish a practical strategy for decoding odorant recognition, offering new insights into olfaction signaling and applications in fragrance and therapeutic development. Structural decoding of reversible covalent linkage of odorants in human olfactory receptor OR6A2.,Wang T, Wu Y, Wang L, Li S, Zhao F, Wu L, Liu Y, Qin J, Tan Q, Liu J, Zeng L, Chen Y, Gao S, Shui W, Zhao S, Hua T, Liu ZJ Cell. 2026 Jan 21:S0092-8674(25)01430-8. doi: 10.1016/j.cell.2025.12.017. PMID:41570822[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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