Structural insights into ligand recognition and activation of the medium-chain fatty acid-sensing receptor GPR84 PMID: 37277332

ADC Targets in Oncology

2026-04-10

Structural insights into ligand recognition and activation of the medium-chain fatty acid-sensing receptor GPR84

Nat Commun. 2023 Jun 6;14(1):3271. doi: 10.1038/s41467-023-38985-6.

Heng Liu ^# ¹ , Qing Zhang ^# ¹ ² ³ ⁴ , Xinheng He ^# ¹ ⁵ , Mengting Jiang ⁶ , Siwei Wang ¹ ⁴ ⁵ , Xiaoci Yan ¹ ² ⁵ , Xi Cheng ¹ ⁵ , Yang Liu ¹ ⁴ , Fa-Jun Nan ¹ ² ³ ⁴ , H Eric Xu ⁷ ⁸ ⁹ ¹⁰ , Xin Xie ¹¹ ¹² ¹³ ¹⁴ ¹⁵ , Wanchao Yin ¹⁶ ¹⁷ ¹⁸

Affiliations

1. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
2. School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, 310024, Hangzhou, China.
3. Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, 264117, Yantai, Shandong, China.
4. National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 201203, Shanghai, China.
5. University of Chinese Academy of Sciences, 100049, Beijing, China.
6. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, 210023, Nanjing, China.
7. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. [email protected].
8. University of Chinese Academy of Sciences, 100049, Beijing, China. [email protected].
9. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, 210023, Nanjing, China. [email protected].
10. School of Life Science and Technology, ShanghaiTech University, 201210, Shanghai, China. [email protected].
11. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. [email protected].
12. School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, 310024, Hangzhou, China. [email protected].
13. Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, 264117, Yantai, Shandong, China. [email protected].
14. National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 201203, Shanghai, China. [email protected].
15. University of Chinese Academy of Sciences, 100049, Beijing, China. [email protected].
16. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. [email protected].
17. University of Chinese Academy of Sciences, 100049, Beijing, China. [email protected].
18. Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 528400, Guangdong, China. [email protected].
# Contributed equally.

Abstract

GPR84 is an orphan class A G protein-coupled receptor (GPCR) that is predominantly expressed in immune cells and plays important roles in inflammation, fibrosis, and metabolism. Here, we present cryo-electron microscopy (cryo-EM) structures of Gα_i protein-coupled human GPR84 bound to a synthetic lipid-mimetic ligand, LY237, or a putative endogenous ligand, a medium-chain fatty acid (MCFA) 3-hydroxy lauric acid (3-OH-C12). Analysis of these two ligand-bound structures reveals a unique hydrophobic nonane tail -contacting patch, which forms a blocking wall to select MCFA-like agonists with the correct length. We also identify the structural features in GPR84 that coordinate the polar ends of LY237 and 3-OH-C12, including the interactions with the positively charged side chain of R172 and the downward movement of the extracellular loop 2 (ECL2). Together with molecular dynamics simulations and functional data, our structures reveal that ECL2 not only contributes to direct ligand binding, but also plays a pivotal role in ligand entry from the extracellular milieu. These insights into the structure and function of GPR84 could improve our understanding of ligand recognition, receptor activation, and Gα_i-coupling of GPR84. Our structures could also facilitate rational drug discovery against inflammation and metabolic disorders targeting GPR84.