Abstract：
:Class B peptide hormone GPCRs are targets for the treatment of major chronic disease. Peptide ligands of these receptors display biased agonism and this may provide future therapeutic advantage. Recent active structures of the calcitonin (CT) and glucagon-like peptide-1 (GLP-1) receptors reveal distinct engagement of peptides with extracellular loops (ECLs) 2 and 3, and mutagenesis of the GLP-1R has implicated these loops in dynamics of receptor activation. In the current study, we have mutated ECLs 2 and 3 of the human CT receptor (CTR), to interrogate receptor expression, peptide affinity and efficacy. Integration of these data with insights from the CTR and GLP-1R active structures, revealed marked diversity in mechanisms of peptide engagement and receptor activation between the CTR and GLP-1R. While the CTR ECL2 played a key role in conformational propagation linked to Gs/cAMP signalling this was mechanistically distinct from that of GLP-1R ECL2. Moreover, ECL3 was a hotspot for distinct ligand- and pathway-specific effects, and this has implications for the future design of biased agonists of class B GPCRs.
journal_name
Biochem Pharmacoljournal_title
Biochemical pharmacologyauthors
Dal Maso E,Zhu Y,Pham V,Reynolds CA,Deganutti G,Hick CA,Yang D,Christopoulos A,Hay DL,Wang MW,Sexton PM,Furness SGB,Wootten Ddoi
10.1016/j.bcp.2018.02.005subject
Has Abstractpub_date
2018-04-01 00:00:00pages
214-244eissn
0006-2952issn
1873-2968pii
S0006-2952(18)30062-5journal_volume
150pub_type
杂志文章abstract：:Stress, be it from environmental factors or intrinsic to the cell as result of growth and metabolism, can be harmful to cells. Mammalian cells have developed numerous mechanisms to respond to diverse forms of stress. These mechanisms combine signaling cascades and activation of gene expression programs to orchestrate ...
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