Na+-mimicking ligands stabilize the inactive state of leukotriene B4 receptor BLT1
| Autor: | Motonao Nakamura, Keitaro Yamashita, Yoshiaki Kawano, Kunio Hirata, Takao Shimizu, Toshiaki Okuno, Masakatsu Hato, Masashi Miyano, Takehiko Yokomizo, Masaki Yamamoto, Shigeyuki Yokoyama, Tetsuya Hori |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Allosteric modulator Chemistry Stereochemistry Leukotriene B4 receptor Cell Biology Benzamidine Amidine 03 medical and health sciences Transmembrane domain chemistry.chemical_compound 030104 developmental biology 0302 clinical medicine Moiety Water cluster Molecular Biology 030217 neurology & neurosurgery G protein-coupled receptor |
| Zdroj: | Nature Chemical Biology. 14:262-269 |
| ISSN: | 1552-4469 1552-4450 |
| Popis: | 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 Asp2.50 inside the seven-transmembrane domain. We determined the crystal structure of the leukotriene B4 (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 D662.50, 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. |
| Databáze: | OpenAIRE |
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