Structure-based mechanism of cysteinyl leukotriene receptor inhibition by antiasthmatic drugs.
Aleksandra LugininaAnastasiia GusachEgor MarinAlexey V MishinRebecca L BrouillettePetr PopovAnna ShiriaevaÉlie Besserer-OffroyJean-Michel LongpréElizaveta LyapinaAndrii IshchenkoNilkanth PatelVitaly PolovinkinNadezhda SafronovaAndrey BogorodskiyEvelina EdelweissHao HuUwe WeierstallWei LiuAlexander BatyukValentin GordeliyGye Won HanPhilippe SarretVsevolod KatritchValentin I BorshchevskiyVadim CherezovPublished in: Science advances (2019)
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.
Keyphrases
- allergic rhinitis
- cardiovascular disease
- end stage renal disease
- chronic kidney disease
- systematic review
- randomized controlled trial
- small molecule
- chronic obstructive pulmonary disease
- papillary thyroid
- newly diagnosed
- type diabetes
- prognostic factors
- oxidative stress
- high throughput
- high resolution
- minimally invasive
- squamous cell carcinoma
- single cell
- gene expression
- dna methylation
- metabolic syndrome
- coronary artery disease
- binding protein
- patient reported
- lymph node metastasis