RRC ID 50085
著者 Hori T, Okuno T, Hirata K, Yamashita K, Kawano Y, Yamamoto M, Hato M, Nakamura M, Shimizu T, Yokomizo T, Miyano M, Yokoyama S.
タイトル Na+-mimicking ligands stabilize the inactive state of leukotriene B4 receptor BLT1.
ジャーナル Nat Chem Biol
Abstract 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.
巻・号 14(3)
ページ 262-269
公開日 2018-3-1
DOI 10.1038/nchembio.2547
PII nchembio.2547
PMID 29309055
MeSH Allosteric Site Amidines / chemistry Animals Aspartic Acid / chemistry Binding Sites Crystallography, X-Ray Drug Design Guinea Pigs HEK293 Cells Humans Inositol Phosphates / chemistry Leukotriene B4 / chemistry Ligands Protein Binding Protein Domains Receptors, Leukotriene B4 / chemistry* Transforming Growth Factor alpha / metabolism
IF 12.587
引用数 29
リソース情報
ヒト・動物細胞 COS-7(RCB0539)