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Structural basis of leukotriene B4 receptor 1 activation

文献类型：期刊论文

作者Wang, Na2; He, Xinheng3,4,5; Zhao, Jing1; Jiang, Hualiang3,4,5; Cheng, Xi3,4,5; Xia, Yu1; Xu, H. Eric3,4,5; He, Yuanzheng2
刊名NATURE COMMUNICATIONS
出版日期2022-03-03
卷号13期号:1页码:10
DOI10.1038/s41467-022-28820-9
通讯作者He, Yuanzheng(ajian.he@hit.edu.cn)
英文摘要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(i) protein in an active conformation at resolution of 2.91 angstrom. 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(3.36) and I271(7.39) 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. In the paper, Dr. Wang et al reported a cryo-EM structure of the human leukotriene B4 receptor 1 (BLT1) in complex with its native ligand leukotriene B4 (LTB4) in an active conformation complexed with Gi protein. The structure reveals the molecule determinant of LTB4 binding and the mechanism of receptor activation. These structural information will boost the understanding of LTB4-BLT1 signaling and provide a rational basis for designing novel anti-leukotriene drugs.
WOS关键词BEAM-INDUCED MOTION ; CRYO-EM STRUCTURE ; CRYSTAL-STRUCTURE ; B-4 ; SOFTWARE ; TOOLS ; ACID
资助项目HIT Center for Life Sciences ; National Natural Science Foundation of China[32070048] ; Ministry of Science and Technology of China[2018YFA0507002] ; Shanghai Municipal Science and Technology Major Project[2019SHZDZX02] ; CAS Strategic Priority Research Program[XDB08020303] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program of China[2018ZX09711002] ; Science and Technology Commission of Shanghai Municipal[20431900100] ; Jack Ma Foundation[2020-CMKYGG-05] ; National Key R&D Program of China[2018YFA0800903]
WOS研究方向Science & Technology - Other Topics
语种英语
WOS记录号WOS:000764258100005
出版者NATURE PORTFOLIO
源URL[http://119.78.100.183/handle/2S10ELR8/299876]  
专题新药研究国家重点实验室
通讯作者He, Yuanzheng
作者单位1.Tsinghua Univ, Dept Chem, MOE Key Lab Bioorgan Phosphorus Chem & Chem Biol, Beijing 100084, Peoples R China
2.Harbin Inst Technol, HIT Ctr Life Sci, Lab Receptor Struct & Signaling, Harbin 150001, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China
5.Univ Chinese Acad Sci, Beijing, Peoples R China
推荐引用方式
GB/T 7714		 Wang, Na,He, Xinheng,Zhao, Jing,et al. Structural basis of leukotriene B4 receptor 1 activation[J]. NATURE COMMUNICATIONS,2022,13(1):10.
APA Wang, Na.,He, Xinheng.,Zhao, Jing.,Jiang, Hualiang.,Cheng, Xi.,...&He, Yuanzheng.(2022).Structural basis of leukotriene B4 receptor 1 activation.NATURE COMMUNICATIONS,13(1),10.
MLA Wang, Na,et al."Structural basis of leukotriene B4 receptor 1 activation".NATURE COMMUNICATIONS 13.1(2022):10.

入库方式： OAI收割

来源：上海药物研究所

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