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

Heng Liu, Qing Zhang, Xinheng He, Mengting Jiang, Siwei Wang, Xiaoci Yan, Xi Cheng, Yang Liu, Fa-Jun Nan, H. Eric Xu (), Xin Xie () and Wanchao Yin ()
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Heng Liu: Chinese Academy of Sciences
Qing Zhang: Chinese Academy of Sciences
Xinheng He: Chinese Academy of Sciences
Mengting Jiang: Nanjing University of Chinese Medicine
Siwei Wang: Chinese Academy of Sciences
Xiaoci Yan: Chinese Academy of Sciences
Xi Cheng: Chinese Academy of Sciences
Yang Liu: Chinese Academy of Sciences
Fa-Jun Nan: Chinese Academy of Sciences
H. Eric Xu: Chinese Academy of Sciences
Xin Xie: Chinese Academy of Sciences
Wanchao Yin: Chinese Academy of Sciences

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: 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 Gαi 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 Gαi-coupling of GPR84. Our structures could also facilitate rational drug discovery against inflammation and metabolic disorders targeting GPR84.

Date: 2023
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Citations: View citations in EconPapers (2)

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DOI: 10.1038/s41467-023-38985-6

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