NDLI: Genetically encoded photocross-linkers determine the biological binding site of exendin-4 peptide in the N-terminal domain of the intact human glucagon-like peptide-1 receptor (GLP-1R)

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Genetically encoded photocross-linkers determine the biological binding site of exendin-4 peptide in the N-terminal domain of the intact human glucagon-like peptide-1 receptor (GLP-1R)

Content Provider	Scilit
Author	Koole, Cassandra Reynolds, Christopher A. Mobarec, Juan C. Hick, Caroline Sexton, Patrick M. Sakmar, Thomas P.
Copyright Year	2017
Description	Journal: Journal of Biological Chemistry The glucagon-like peptide-1 receptor (GLP-1R) is a key therapeutic target in the management of type II diabetes mellitus, with actions including regulation of insulin biosynthesis and secretion, promotion of satiety, and preservation of β-cell mass. Like most class B G protein-coupled receptors (GPCRs), there is limited knowledge linking biological activity of the GLP-1R with the molecular structure of an intact, full-length, and functional receptor·ligand complex. In this study, we have utilized genetic code expansion to site-specifically incorporate the photoactive amino acid p-azido-l-phenylalanine (azF) into N-terminal residues of a full-length functional human GLP-1R in mammalian cells. UV-mediated photolysis of azF was then carried out to induce targeted photocross-linking to determine the proximity of the azido group in the mutant receptor with the peptide exendin-4. Cross-linking data were compared directly with the crystal structure of the isolated N-terminal extracellular domain of the GLP-1R in complex with exendin(9–39), revealing both similarities as well as distinct differences in the mode of interaction. Generation of a molecular model to accommodate the photocross-linking constraints highlights the potential influence of environmental conditions on the conformation of the receptor·peptide complex, including folding dynamics of the peptide and formation of dimeric and higher order oligomeric receptor multimers. These data demonstrate that crystal structures of isolated receptor regions may not give a complete reflection of peptide/receptor interactions and should be combined with additional experimental constraints to reveal peptide/receptor interactions occurring in the dynamic, native, and full-length receptor state.
Related Links	http://www.jbc.org/content/292/17/7131.full.pdf https://core.ac.uk/download/pdf/83927368.pdf https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5409479/pdf http://www.jbc.org/article/S0021925820429011/pdf
Ending Page	7144
Page Count	14
Starting Page	7131
ISSN	00219258
e-ISSN	1083351X
DOI	10.1074/jbc.m117.779496
Journal	Journal of Biological Chemistry
Issue Number	17
Volume Number	292
Language	English
Publisher	Elsevier BV
Publisher Date	2017-04-01
Access Restriction	Open
Subject Keyword	Journal: Journal of Biological Chemistry Biochemistry and Molecular Biology G Protein-coupled Receptor (gpcr) Molecular Modeling Structural Biology Structure-function Glucagon-like Peptide-1 Receptor (glp-1r) Genetic Code Expansion Photocross-linking Unnatural Amino Acid
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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Genetically encoded photocross-linkers determine the biological binding site of exendin-4 peptide in the N-terminal domain of the intact human glucagon-like peptide-1 receptor (GLP-1R)

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Genetically encoded photocross-linkers determine the biological binding site of exendin-4 peptide in the N-terminal domain of the intact human glucagon-like peptide-1 receptor (GLP-1R)

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Genetically encoded photocross-linkers determine the biological binding site of exendin-4 peptide in the N-terminal domain of the intact human glucagon-like peptide-1 receptor (GLP-1R)