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

Cysteinyl leukotriene G protein-coupled receptors CysLT₁ and CysLT₂ regulate pro-inflammatory responses associated with allergic disorders. While selective inhibition of CysLT₁R has been used for treating asthma and associated diseases for over two decades, CysLT₂R 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 CysLT₂R in complex with three dual CysLT₁R/CysLT₂R 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.