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Cryo-EM structures of Drosophila OR67d–Orco complexes reveal insect pheromone sensing mechanism

Jiangqin Wang^1,2,3,† , Chuanyan Yang^4,† , Shenghai Chang^5,† , Dian Jiao^1,2,† , Jiahao Lin^6,7 , Xiaotong Yang⁴ , Weijie Cai⁴ , Demin Ma^1,4 , Zhong Jie Ding⁸ , Jia Huang⁹ , Jianhua Huang⁹ , Minrui Fan¹⁰ , Meiqin Hu⁴ , Yong Wang^6,7,* , Haoxing Xu^4,11,* , Nannan Su^3,* , Jiangtao Guo^{1,2,8,12,13,*}

¹Department of Neurology of the Fourth Affiliated Hospital, and Department of Biophysics, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
²Nanhu Braincomputer Interface Institute, Hangzhou, Zhejiang, China
³Center for Membrane Receptors and Brain Medicine, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, Zhejiang, China
⁴New Cornerstone Science Laboratory and Liangzhu Laboratory, the Second Affiliated Hospital and School of Basic Medical Sciences, Zhejiang University, Hangzhou, Zhejiang, China
⁵Center of Cryo-Electron Microscopy, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
⁶College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang, China
⁷The Provincial International Science and Technology Cooperation Base on Engineering Biology, International Campus of Zhejiang University, Haining, Zhejiang, China
⁸State Key Laboratory of Plant Environmental Resilience, College of Life Science, Zhejiang University, Hangzhou, Zhejiang, China
⁹Ministry of Agriculture Key Laboratory of Molecular Biology of Crop Pathogens and Insects, Institute of Insect Sciences, College of Agriculture and Biotechnology, Zhejiang University, Hangzhou, Zhejiang, China
¹⁰CAS Center for Excellence in Molecular Plant Sciences, Institute of Plant Physiology and Ecology, Chinese Academy of Sciences, Shanghai, China
¹¹Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI, USA
¹²NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Center for Brain Science and Brain-machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, Hangzhou, Zhejiang, China
¹³Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China
^†These authors contributed equally: Jiangqin Wang, Chuanyan Yang, Shenghai Chang, Dian Jiao
* Correspondence: Yong Wang(yongwang_isb@zju.edu.cn)Haoxing Xu(haoxingx@zju.edu.cn)Nannan Su(sunannan@zju.edu.cn)Jiangtao Guo(jiangtaoguo@zju.edu.cn)

Pheromones mediate intraspecific communication to regulate the physiology and behavior of animals, particularly insects. The detection of pheromones is initiated by the binding of pheromone molecules, e.g., 11-cis-vaccenyl acetate (cVA) in Drosophila, to specific receptor proteins in chemosensory neurons, but the underlying molecular mechanisms remain unclear. Here, we report structures of Drosophila pheromone receptor OR67d–Orco complexes in apo closed, pheromone-bound open, and synthetic agonist VUAA1-bound open conformations. OR67d and Orco assemble into a hetero-tetrameric channel with a 1:3 stoichiometry. In OR67d, the inverted L-shaped cVA or its analog binds into a deep and bent hydrophobic pocket, inducing both local and global conformational changes that lead to an asymmetrical opening of the channel gate. By comparison, VUAA1 binds to Orco instead of OR67d to cause a similar asymmetrical opening. Together, our studies reveal the structural basis for pheromone activation of hetero-tetrameric pheromone receptors.

https://doi.org/10.1038/s41422-026-01264-2

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