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Molecular basis for kinin selectivity and activation of the human bradykinin receptors

By Yu-Ling Yin, Chenyu Ye, Fulai Zhou, Jia Wang, Dehua Yang, Wanchao Yin, Ming-Wei Wang, H. Eric Xu, Yi Jiang

Posted 29 May 2021
bioRxiv DOI: 10.1101/2021.05.27.446069

Bradykinin and kallidin are endogenous kinin peptide hormones that belong to the kallikrein-kinin system and are essential to the regulation of blood pressure, inflammation, coagulation, and pain control. Des-Arg10-kallidin, the carboxy-terminal des-Arg metabolite of kallidin, and bradykinin selectively activate two G protein-coupled receptors, type 1 and type 2 bradykinin receptors (B1R and B2R), respectively. The hyperactivation of bradykinin receptors, termed bradykinin storm, is associated with pulmonary edema in COVID-19 patients, suggesting that bradykinin receptors are important targets for COVID-19 intervention. Here we report two G protein complex structures of B1R and B2R bound to des-Arg10-kallidin and bradykinin. Combined with functional analysis, our structures reveal the mechanism of ligand selectivity and specific activation of the bradykinin receptor. These findings also provide a framework for guiding drug design targeting bradykinin receptors for the treatment of inflammation, cardiovascular disorders, and COVID-19.

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