Does Divergent Binding Pocket Closure Drive Ligand Bias for Class A GPCRs?

GPCRs couple to intracellular transducer proteins, which reciprocally closes the extracellular ligand binding pocket, a process called allosteric coupling. Biased agonists preferentially stimulate receptor coupling to specific signaling pathways. Here, we postulate that agonists with extended bindin...

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Bibliographic Details
Published in:Trends in pharmacological sciences (Regular ed.) 2019-04, Vol.40 (4), p.236-239
Main Authors: Bermudez, Marcel, Bock, Andreas
Format: Article
Language:English
Subjects:
allosteric coupling
biased signaling
drug design
extended binding mode
GPCR
ligand bias
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Summary:GPCRs couple to intracellular transducer proteins, which reciprocally closes the extracellular ligand binding pocket, a process called allosteric coupling. Biased agonists preferentially stimulate receptor coupling to specific signaling pathways. Here, we postulate that agonists with extended binding modes selectively interfere with binding pocket closure, which results in divergent allosteric coupling, eventually leading to ligand bias.
ISSN:0165-6147
1873-3735
DOI:10.1016/j.tips.2019.02.005