Structural basis of amine odorant perception by a mammal olfactory receptor

Lulu Guo, Jie Cheng, Shuo Lian, Qun Liu, Yan Lu, Yuan Zheng, Kongkai Zhu, Minghui Zhang, Yalei Kong, Chao Zhang, Naikang Rong, Yuming Zhuang, Guoxing Fang, Jingjing Jiang, Tianyao Zhang, Xiang Han, Zili Liu, Ming Xia, Shangming Liu, Lei Zhang, Stephen D. Liberles, Xiao Yu, Yunfei Xu (), Fan Yang (), Qian Li () and Jin-Peng Sun ()
Additional contact information
Lulu Guo: Shandong University
Jie Cheng: Shandong University
Shuo Lian: Qilu Hospital of Shandong University
Qun Liu: Shandong University School of Medicine
Yan Lu: Shandong University School of Medicine
Yuan Zheng: School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education
Kongkai Zhu: Shandong University
Minghui Zhang: Qilu Hospital of Shandong University
Yalei Kong: Shanghai Jiao Tong University School of Medicine
Chao Zhang: Shandong University School of Medicine
Naikang Rong: Shandong University School of Medicine
Yuming Zhuang: Shandong University School of Medicine
Guoxing Fang: Shandong University School of Medicine
Jingjing Jiang: Shandong University School of Medicine
Tianyao Zhang: Shandong University School of Medicine
Xiang Han: Shandong University
Zili Liu: Shandong University School of Medicine
Ming Xia: Shandong Provincial Hospital Affiliated to Shandong First Medical University
Shangming Liu: Shandong University
Lei Zhang: Xi’an Jiaotong University
Stephen D. Liberles: Harvard Medical School
Xiao Yu: Shandong University
Yunfei Xu: Qilu Hospital of Shandong University
Fan Yang: Shandong University
Qian Li: Shanghai Jiao Tong University School of Medicine
Jin-Peng Sun: Shandong University

Nature, 2023, vol. 618, issue 7963, 193-200

Abstract: Abstract Odorants are detected as smell in the nasal epithelium of mammals by two G-protein-coupled receptor families, the odorant receptors and the trace amine-associated receptors1,2 (TAARs). TAARs emerged following the divergence of jawed and jawless fish, and comprise a large monophyletic family of receptors that recognize volatile amine odorants to elicit both intraspecific and interspecific innate behaviours such as attraction and aversion3–5. Here we report cryo-electron microscopy structures of mouse TAAR9 (mTAAR9) and mTAAR9–Gs or mTAAR9–Golf trimers in complex with β-phenylethylamine, N,N-dimethylcyclohexylamine or spermidine. The mTAAR9 structures contain a deep and tight ligand-binding pocket decorated with a conserved D3.32W6.48Y7.43 motif, which is essential for amine odorant recognition. In the mTAAR9 structure, a unique disulfide bond connecting the N terminus to ECL2 is required for agonist-induced receptor activation. We identify key structural motifs of TAAR family members for detecting monoamines and polyamines and the shared sequence of different TAAR members that are responsible for recognition of the same odour chemical. We elucidate the molecular basis of mTAAR9 coupling to Gs and Golf by structural characterization and mutational analysis. Collectively, our results provide a structural basis for odorant detection, receptor activation and Golf coupling of an amine olfactory receptor.

Date: 2023
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DOI: 10.1038/s41586-023-06106-4

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