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  • Our structures also provide new insights into CRTH

    2019-08-15

    Our structures also provide new insights into CRTH2 drug development. The ligand binding pocket revealed by our structures comprises many aromatic residues and a few polar residues at the distal end. Correspondingly, most CRTH2 antagonists share a similar structural feature characterized by an acetate polar group attached to a central aromatic group to fit the ligand binding pocket (Pettipher and Whittaker, 2012). The different binding poses of the tail groups of CAY10471 and fevipiprant associated with the different conformations of W2837.32 and the N-loop indicate that the open end of the ligand binding pocket, which we propose to be the ligand entry port, exhibits certain structural flexibility. Additional structures of CRTH2 with other antagonists that have distinct tail groups are needed to further investigate the conformational Atglistatin of residues in this region, as it may significantly affect the results of structure-based virtual screening for developing novel CRTH2 antagonists. Furthermore, the unexpected small molecules modeled in this region suggest that the ligand entry port may offer an additional site for designing new synthetic CRTH2 antagonists, which compared to CAY10471 and fevipiprant would engage in additional interactions with the receptor to achieve stronger binding and a longer duration of action. Collectively, our structures offer novel structural insights into the action of diverse CRTH2 antagonists, which will facilitate CRTH2 drug development for a number of inflammatory diseases, including asthma. They also reveal interesting features of the ligand binding pocket and suggest a novel mechanism for the binding of the endogenous lipid molecule PGD2, thus shedding light on the structural and mechanistic diversity of GPCRs for the recognition of lipid mediators.
    STAR★Methods
    Acknowledgments We thank the staff at the GM/CA at APS of Argonne National Laboratory at Chicago for their assistance with X-ray diffraction data collection. We thank Dr. James C. Burnett and Dr. Peter Wipf for discussion. We acknowledge the financial support from the University of Pittsburgh, the NIH (Maximizing Investigators’ Research Award [MIRA] R351R35GM128641 to C.Z.), the Biomedical Research Council ( to R.N.V.K.D. and H.F.), and the National Natural Science Foundation of China (31770791 and 315707410 to Z.W.). Z.W. is also supported by the startup funds from Southern University of Science and Technology and the Recruitment Program of Global Youth Experts of China.
    CRTH2 – history and clinical potential Ironically, the purported TP antagonist ramatroban (BAY u 3405) which had already been marketed in Japan as a treatment of allergic rhinitis, was also revealed to be a potent CRTH2 antagonist [34].
    CRTH2 beyond allergy and asthma Meanwhile, CRTH2 has been found to be expressed on several additional cell types and in different tissues suggesting that the PGD2/CRTH2 axis might be of potential relevance beyond allergy and asthma. Although the role of PGD2 in a Th2-biased inflammation is well established, investigation of its function in other groups of inflammatory reactions in experimental mouse models is confounded by differential expression patterns of CRTH2 in mice and humans: While CRTH2 can be used as an exclusive marker for Th2 cells in humans, CRTH2-positive Th1 cells as well as neutrophils are present in mice. These differences have to be taken into consideration when drawing conclusions from studies exclusively based on mouse data. A detailed summary of the presence or absence of CRTH2 on various cells types can be found in Table 1.
    Conclusion With a plethora of actions, CRTH2-mediated effects are apparent in almost every tissue of the human body (Fig. 1). There is growing evidence that CRTH2 plays important roles in allergic inflammation of the respiratory tract and the skin; however, this does not exclude it from being a potential therapeutic target in other conditions, too. These might comprise inflammatory bowel disease, mood disturbances or even cognitive dysfunction on the one hand, and autoimmune disease such as rheumatoid arthritis, and lung and kidney fibrosis, on the other hand. In male-type baldness, CRTH2 antagonists might already be on the crossroads to becoming available for patients, soon.