7VKT

cryo-EM structure of LTB4-bound BLT1 in complex with Gi protein

7VKT の概要

• エントリーDOI: 10.2210/pdb7vkt/pdb
• EMDBエントリー: 32018
• 分子名称: Leukotriene B4 receptor 1, Guanine nucleotide-binding protein G(i) subunit alpha-1, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, ... (9 entities in total)
• 機能のキーワード: gpcr, membrane protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 5
• 化学式量合計: 153328.92

構造登録者

He, Y.,Wang, N. (登録日: 2021-10-01, 公開日: 2022-03-09, 最終更新日: 2024-11-13)

主引用文献

Wang, N.,He, X.,Zhao, J.,Jiang, H.,Cheng, X.,Xia, Y.,Eric Xu, H.,He, Y.
Structural basis of leukotriene B4 receptor 1 activation.
Nat Commun, 13:1156-1156, 2022

PubMed 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 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.

PubMed: 35241677
DOI: 10.1038/s41467-022-28820-9

実験手法

ELECTRON MICROSCOPY (2.9 Å)