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- Title
The orthosteric agonist-binding pocket in the prototypic class B G-protein-coupled secretin receptor.
- Authors
Miller, Laurence J.; Dong, Maoqing
- Abstract
Class B GPCRs (G-protein-coupled receptors) share heptahelical topology and G-protein binding with other superfamily members, yet have unique structures and modes of activation. Natural ligands for these receptors are moderate-length peptides with C-terminal α-helices. NMR and crystal structures of the peptidebound disulfide-bonded receptor N-terminal domains demonstrate that these helices occupy a conserved groove; however, the details of this interaction vary from one receptor to another. In this review, we focus on the prototypic secretin receptor and use extensive intrinsic photoaffinity labelling, structure-activity series, alanine-replacementmutagenesis and fluorescence analysis to define themolecular basis for this interaction. Additionally, experimental validation of predictions coming from in silico molecular modelling has provided a basis for enhancement of binding affinity. Such insights will be useful in the rational development of drugs acting at this important group of targets.
- Subjects
LIGAND binding (Biochemistry); G protein coupled receptors; PROTOTYPES; SECRETIN; CONFORMATIONAL analysis; MOLECULAR models; CRYSTAL structure
- Publication
Biochemical Society Transactions, 2013, Vol 41, Issue 1, p154
- ISSN
0300-5127
- Publication type
Article
- DOI
10.1042/BST20120204