期刊
NATURE CHEMICAL BIOLOGY
卷 14, 期 3, 页码 262-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/NCHEMBIO.2547
关键词
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资金
- Platform Project for Supporting Drug Discovery and Life Science Research - Japan Agency for Medical Research and Development (AMED)
- Takeda Science Foundation
- MEXT/JSPS KAKENHI [23770133, 15KK0320, 16K08596, 26460061, 15H05897, 15H05904, 15H04708]
- Foundation of Strategic Research Projects in Private Universities from MEXT [S1311011, S1411007]
- Takeda Pharmaceutical Co.
- Grants-in-Aid for Scientific Research [26460061, 15H05904, 15H04708, 23770133, 15KK0320, 16K08596, 15H05897] Funding Source: KAKEN
Most G-protein-coupled receptors (GPCRs) are stabilized in common in the inactive state by the formation of the sodium ion-centered water cluster with the conserved Asp(2.50) inside the seven-transmembrane domain. We determined the crystal structure of the leukotriene B-4 (LTB4) receptor BLT1 bound with BIIL260, a chemical bearing a benzamidine moiety. Surprisingly, the amidine group occupies the sodium ion and water locations, interacts with D66(2.50), and mimics the entire sodium ion-centered water cluster. Thus, BLT1 is fixed in the inactive state, and the transmembrane helices cannot change their conformations to form the active state. Moreover, the benzamidine molecule alone serves as a negative allosteric modulator for BLT1. As the residues involved in the benzamidine binding are widely conserved among GPCRs, the unprecedented inverse-agonist mechanism by the benzamidine moiety could be adapted to other GPCRs. Consequently, the present structure will enable the rational development of inverse agonists specific for each GPCR.
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