Abstract：
:Ligand-directed signal bias offers opportunities for sculpting molecular events, with the promise of better, safer therapeutics. Critical to the exploitation of signal bias is an understanding of the molecular events coupling ligand binding to intracellular signaling. Activation of class B G protein-coupled receptors is driven by interaction of the peptide N terminus with the receptor core. To understand how this drives signaling, we have used advanced analytical methods that enable separation of effects on pathway-specific signaling from those that modify agonist affinity and mapped the functional consequence of receptor modification onto three-dimensional models of a receptor-ligand complex. This yields molecular insights into the initiation of receptor activation and the mechanistic basis for biased agonism. Our data reveal that peptide agonists can engage different elements of the receptor extracellular face to achieve effector coupling and biased signaling providing a foundation for rational design of biased agonists.
journal_name
Celljournal_title
Cellauthors
Wootten D,Reynolds CA,Smith KJ,Mobarec JC,Koole C,Savage EE,Pabreja K,Simms J,Sridhar R,Furness SGB,Liu M,Thompson PE,Miller LJ,Christopoulos A,Sexton PMdoi
10.1016/j.cell.2016.05.023subject
Has Abstractpub_date
2016-06-16 00:00:00pages
1632-1643issue
7eissn
0092-8674issn
1097-4172pii
S0092-8674(16)30571-2journal_volume
165pub_type
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