The G protein-coupled cysteinyl leukotriene receptor CysLT1R mediates inflammatory processes and plays a major role in numerous disorders, including asthma, allergic rhinitis, cardiovascular disease, and cancer. Selective CysLT1R antagonists are widely prescribed as antiasthmatic drugs; however, these drugs demonstrate low effectiveness in some patients and exhibit a variety of side effects. To gain deeper understanding into the functional mechanisms of CysLTRs, we determined the crystal structures of CysLT1R bound to two chemically distinct antagonists, zafirlukast and pranlukast. The structures reveal unique ligand-binding modes and signaling mechanisms, including lateral ligand access to the orthosteric pocket between transmembrane helices TM4 and TM5, an atypical pattern of microswitches, and a distinct four-residue-coordinated sodium site. These results provide important insights and structural templates for rational discovery of safer and more effective drugs.

Biodesign Center for Applied Structural Discovery Biodesign Institute Arizona State University Tempe AZ 85287 USA

Department of Pharmacology Physiology Faculty of Medicine and Health Sciences Institut de Pharmacologie de Sherbrooke Université de Sherbrooke Quebec J1H 5N4 Canada

Department of Physics Arizona State University Tempe AZ 85287 USA

Departments of Chemistry and Biological Sciences Bridge Institute University of Southern California Los Angeles CA 90089 USA

ELI Beamlines Institute of Physics Czech Academy of Sciences 18221 Prague Czech Republic

Institut de Biologie Structurale J P Ebel Université Grenoble Alpes CEA CNRS Grenoble 38000 France

Institute of Complex Systems ICS 6 Structural Biochemistry Research Centre Juelich Juelich Germany

Institute of Crystallography RWTH Aachen University Aachen Germany

Juelich Center for Structural Biology Research Center Juelich Juelich Germany

Linac Coherent Light Source SLAC National Accelerator Laboratory Menlo Park CA 94025 USA

Research Center for Molecular Mechanisms of Aging and Age Related Diseases Moscow Institute of Physics and Technology Dolgoprudny 141701 Russia

School of Molecular Sciences Arizona State University Tempe AZ 85287 USA

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