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 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 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.

大多数的G蛋白偶联受体（GPCR）在非活性状态下都可以通过在七个跨膜结构域内形成具有守恒的Asp ^2.50的钠离子为中心的水簇而稳定下来。我们确定与BIIL260结合的白三烯B ₄（LTB ₄）受体BLT1的晶体结构，BIIL260是带有苄bearing部分的化学物质。出人意料的是，the基占据了钠离子和水的位置，与D66 ^2.50相互作用，并模仿整个以钠离子为中心的水团簇。因此，BLT1被固定在非活动状态，并且跨膜螺旋不能改变其构象以形成活动状态。此外，苯甲idine分子单独充当BLT1的负变构调节剂。由于参与苯甲idine键合的残基在GPCR中被广泛保守，因此苯甲idine基团前所未有的反向激动剂机制可适用于其他GPCR。因此，本结构将使得能够合理开发针对每个GPCR的反向激动剂。