Structural basis of ligand selectivity and disease mutations in cysteinyl leukotriene receptors

Cysteinyl leukotriene G protein-coupled receptors CysLT(1) and CysLT(2) regulate pro-inflammatory responses associated with allergic disorders. While selective inhibition of CysLT(1)R has been used for treating asthma and associated diseases for over two decades, CysLT(2)R has recently started to emerge as a potential drug target against atopic asthma, brain injury and central nervous system disorders, as well as several types of cancer. Here, we describe four crystal structures of CysLT(2)R in complex with three dual CysLT(1)R/CysLT(2)R antagonists. The reported structures together with the results of comprehensive mutagenesis and computer modeling studies shed light on molecular determinants of CysLTR ligand selectivity and specific effects of disease-related single nucleotide variants.