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-Structure paper
タイトル | Structural basis of leukotriene B4 receptor 1 activation. |
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ジャーナル・号・ページ | Nat Commun, Vol. 13, Issue 1, Page 1156, Year 2022 |
掲載日 | 2022年3月3日 |
著者 | Na Wang / Xinheng He / Jing Zhao / Hualiang Jiang / Xi Cheng / Yu Xia / H Eric Xu / Yuanzheng He / |
PubMed 要旨 | 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) ...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 G 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 M101 and I271 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. |
リンク | Nat Commun / PubMed:35241677 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 2.9 Å |
構造データ | EMDB-32018, PDB-7vkt: |
化合物 | ChemComp-LTB: ChemComp-Y01: ChemComp-8IO: ChemComp-HOH: |
由来 |
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キーワード | MEMBRANE PROTEIN / GPCR |