Structural basis of leukotriene B4 receptor 1 activation

• DOI: 10.1038/s41467-022-28820-9
• Publication Date: 2022-03-03T11:05:35Z
• Authors: Na Wang; Xinheng He; Jing Zhao; Hualiang Jiang; Xi Cheng; Yu Xia; H. Eric Xu; Yuanzheng He
• Keywords: Leukotriene B4; Docking (animal); Drug Design; Rational design

Abstract Leukotriene B4 receptor 1 (BLT1) plays crucial roles in the acute inflammatory responses and is a valuable target for anti-inflammation treatment, however, mechanism by which leukotriene (LTB4) activates remains unclear. Here, we report cryo-electron microscopy (cryo-EM) structure of LTB4 -bound human BLT1 complex with G i protein an active conformation at resolution 2.91 Å. In combination molecule dynamics (MD) simulation, docking site-directed mutagenesis, our reveals that hydrogen-bond network water molecules key polar residues molecular determinant binding. We also find displacement M101 3.36 I271 7.39 to center receptor, unlock ion lock lower part pocket, activation. addition, reveal binding site phosphatidylinositol (PI) discover widely open ligand pocket may contribute lack specificity efficacy current BLT1-targeting drug design. Taken together, structural analysis provides scaffold understanding activation rational basis designing anti-leukotriene drugs.