Structural decoding of reversible covalent linkage of odorants in human olfactory receptor OR6A2

  • Cell. 2026 Mar 5;189(5):1451-1464.e27. doi: 10.1016/j.cell.2025.12.017.
Tian Wang  1 ,  Yiran Wu  2 ,  Ling Wang  2 ,  Shanshan Li  2 ,  Fei Zhao  2 ,  Lijie Wu  2 ,  Yue Liu  1 ,  Jingzi Qin  1 ,  Qiwen Tan  2 ,  Junlin Liu  2 ,  Liting Zeng  1 ,  Yilin Chen  1 ,  Shenyuan Gao  3 ,  Wenqing Shui  1 ,  Suwen Zhao  4 ,  Tian Hua  5 ,  Zhi-Jie Liu  6
Affiliations
  • 1. iHuman Institute, ShanghaiTech University, Shanghai, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
  • 2. iHuman Institute, ShanghaiTech University, Shanghai, China.
  • 3. School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
  • 4. iHuman Institute, ShanghaiTech University, Shanghai, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, China. Electronic address: [email protected].
  • 5. iHuman Institute, ShanghaiTech University, Shanghai, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, China. Electronic address: [email protected].
  • 6. iHuman Institute, ShanghaiTech University, Shanghai, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, China. Electronic address: [email protected].
PMID: 41570822 DOI: 10.1016/j.cell.2025.12.017
Abstract

Olfactory 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 K4.60, validated by mass spectrometry. By integrating structures of consOR6, molecular dynamics simulations, and functional assays, we identified a conserved D45.51Y6.55Y7.41 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.

Keywords
GPCR; OR6; OR6A2; Schiff base linkage; aldehydes; olfactory receptors.
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