2. Academic Validation
  3. Structural decoding of reversible covalent linkage of odorants in human olfactory receptor OR6A2

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

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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