Structural basis of leukotriene B4 receptor 1 activation

Na Wang, Xinheng He, Jing Zhao, Hualiang Jiang, Xi Cheng, Yu Xia, H. Eric Xu and Yuanzheng He ()
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Na Wang: Harbin Institute of Technology
Xinheng He: Chinese Academy of Sciences
Jing Zhao: Tsinghua University
Hualiang Jiang: Chinese Academy of Sciences
Xi Cheng: Chinese Academy of Sciences
Yu Xia: Tsinghua University
H. Eric Xu: Chinese Academy of Sciences
Yuanzheng He: Harbin Institute of Technology

Nature Communications, 2022, vol. 13, issue 1, 1-10

Abstract: Abstract Leukotriene B4 receptor 1 (BLT1) plays crucial roles in the acute inflammatory responses and is a valuable target for anti-inflammation treatment, however, the mechanism by which leukotriene B4 (LTB4) activates receptor remains unclear. Here, we report the cryo-electron microscopy (cryo-EM) structure of the LTB4 -bound human BLT1 in complex with a Gi protein in an active conformation at resolution of 2.91 Å. In combination of molecule dynamics (MD) simulation, docking and site-directed mutagenesis, our structure reveals that a hydrogen-bond network of water molecules and key polar residues is the key molecular determinant for LTB4 binding. We also find that the displacement of residues M1013.36 and I2717.39 to the center of receptor, which unlock the ion lock of the lower part of pocket, is the key mechanism of receptor activation. In addition, we reveal a binding site of phosphatidylinositol (PI) and discover that the widely open ligand binding pocket may contribute the lack of specificity and efficacy for current BLT1-targeting drug design. Taken together, our structural analysis provides a scaffold for understanding BLT1 activation and a rational basis for designing anti-leukotriene drugs.

Date: 2022
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DOI: 10.1038/s41467-022-28820-9

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