[3dem] FREE WEBINAR: Structural Biology and Drug Innovation for β-adrenergic Receptors (Oct 25th)

[qupeng at shuimubio.com]

Dear All,

 

Please join us for the upcoming online webinar at 9:30am EST, Oct 25th 2021.
Click here <https://urldefense.proofpoint.com/v2/url?u=https-3A__zoom.us_webinar_register_WN-5FL3GD6DG5RcG3-5F0C3SYIF8w&d=DwIFCQ&c=-35OiAkTchMrZOngvJPOeA&r=L7-zyQ-04fFCMRqzLIOnx7H0exGZHwIQe_wMPuY600I&m=xghRVxDgBf-gjRaX1b7TkIVoeYDwDwiYSeHS1e8WWj0&s=mzsgU6GeI44vC8zR7hgGHkX6XkZq2UcfJDWQqRYVt68&e= >  for
registration. 

 

Speaker: Prof. Xiangyu Liu

 

Abstract: Beta adrenergic receptors (βARs) mediate physiologic responses to
the catecholamines epinephrine and norepinephrine released by the
sympathetic nervous system. While the hormone epinephrine binds β1AR and
β2AR with similar affinity, the smaller neurotransmitter norepinephrine is
approximately 10-fold selective for the β1AR. To understand the structural
basis for this physiologically important selectivity, we solved the crystal
structures of the human β1AR bound to different antagonists and agonists
including norepinephrine and epinephrine. Structural comparison revealed
that the catecholamine binding pockets are identical between β1AR and β2AR,
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 β2AR over the β1AR. The results suggest it's possible to
develop selective drugs for receptors with identical orthosteric binding
pockets.

 

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
β2AR.

 

Best Regards, 

Peng

--

Peng Qu, MBA, PMP

Director of Business Development 

Shuimu BioSciences

+1 617-599-3866

qupeng at shuimubio.com

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