<html xmlns:v="urn:schemas-microsoft-com:vml" xmlns:o="urn:schemas-microsoft-com:office:office" xmlns:w="urn:schemas-microsoft-com:office:word" xmlns:m="http://schemas.microsoft.com/office/2004/12/omml" xmlns="http://www.w3.org/TR/REC-html40"><head><meta http-equiv=Content-Type content="text/html; charset=iso-8859-7"><meta name=Generator content="Microsoft Word 15 (filtered medium)"><style><!--
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</o:shapelayout></xml><![endif]--></head><body lang=EN-US link="#0563C1" vlink="#954F72" style='word-wrap:break-word'><div class=WordSection1><p class=MsoNormal>Dear All,<o:p></o:p></p><p class=MsoNormal><o:p> </o:p></p><p class=MsoNormal>Please join us for the upcoming online webinar at 9:30am EST, Oct 25<sup>th</sup> 2021. <a href="https://urldefense.proofpoint.com/v2/url?u=https-3A__zoom.us_webinar_register_WN-5FL3GD6DG5RcG3-5F0C3SYIF8w&d=DwMFCQ&c=-35OiAkTchMrZOngvJPOeA&r=L7-zyQ-04fFCMRqzLIOnx7H0exGZHwIQe_wMPuY600I&m=xghRVxDgBf-gjRaX1b7TkIVoeYDwDwiYSeHS1e8WWj0&s=mzsgU6GeI44vC8zR7hgGHkX6XkZq2UcfJDWQqRYVt68&e=">Click here</a> for registration. <o:p></o:p></p><p class=MsoNormal><o:p> </o:p></p><p class=MsoNormal>Speaker: Prof. Xiangyu Liu<o:p></o:p></p><p class=MsoNormal><o:p> </o:p></p><p class=MsoNormal>Abstract: Beta adrenergic receptors (âARs) mediate physiologic responses to the catecholamines epinephrine and norepinephrine released by the sympathetic nervous system. While the hormone epinephrine binds â1AR and â2AR with similar affinity, the smaller neurotransmitter norepinephrine is approximately 10-fold selective for the â1AR. To understand the structural basis for this physiologically important selectivity, we solved the crystal structures of the human â1AR bound to different antagonists and agonists including norepinephrine and epinephrine. Structural comparison revealed that the catecholamine binding pockets are identical between â1AR and â2AR, but the extracellular vestibules have different shapes and electrostatic properties. Metadynamics simulations and mutagenesis studies revealed that these differences influence the path norepinephrine takes to the orthosteric pocket and contribute to the different association rates and thus different affinities. To examine the effect of conformation restriction on ligand binding kinetics and ligand affinity, we developed a rigidified epinephrine. To our surprise, the rigidified epinephrine exhibited over 100 fold preference for the â2AR over the â1AR. The results suggest it’s possible to develop selective drugs for receptors with identical orthosteric binding pockets.<o:p></o:p></p><p class=MsoNormal><o:p> </o:p></p><p class=MsoNormal>While it’s possible to develop subtype selective drugs targeting the orthosteric pockets, the efforts are still highly challenging due to the high homology of the orthosteric binding pockets among different subtypes of receptors. Allosteric modulators are more likely to be selective because they bind to less conserved allosteric binding sites. I will also introduce our work on identifying the binding pockets for the first negative allosteric modulator and the first positive allosteric modulator of the â2AR.<o:p></o:p></p><p class=MsoNormal><o:p> </o:p></p><p class=MsoNormal>Best Regards, <o:p></o:p></p><p class=MsoNormal>Peng<o:p></o:p></p><div><p class=MsoNormal>--<o:p></o:p></p><p class=MsoNormal>Peng Qu, MBA, PMP<o:p></o:p></p><p class=MsoNormal>Director of Business Development <o:p></o:p></p><p class=MsoNormal>Shuimu BioSciences<o:p></o:p></p><p class=MsoNormal>+1 617-599-3866<o:p></o:p></p></div><p class=MsoNormal>qupeng@shuimubio.com<o:p></o:p></p></div></body></html>