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M106692200v1
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Papers In Press, published online ahead of print August 9, 2001
J. Biol. Chem, 10.1074/jbc.M106692200
Submitted on July 16, 2001
Revised on August 9, 2001
Accepted on August 8, 2001

A small molecule ligand of the glucagon-like peptide 1 receptor targets its amino-terminal hormone binding domain

Elmi C. Tibaduiza, Ci Chen, and Martin Beinborn

Molecular Pharmacology Research Center, New England Medical Center, Boston, MA 02111

Corresponding Author: mbeinborn{at}lifespan.org

The glucagon-like peptide receptor (GLP-1R) belongs to a distinct subgroup of G-protein coupled peptide hormone receptors (class B) that has been difficult to target by small molecule drugs. Here, we report that a non-peptide compound, T-0632, binds with micromolar affinity to the human GLP-1R and blocks GLP-1 induced cAMP production. Furthermore, the observation that T-0632 has almost 100-fold selectivity for the human vs. the highly homologous rat GLP-1R provided an opportunity to map determinants of non-peptide binding. Radioligand competition experiments utilizing a series of chimeric human/rat GLP-1R constructs revealed that partial substitution of the amino terminus of the rat GLP-1 R with corresponding sequence from the human homolog was sufficient to confer high T-0632 affinity. Followup analysis of receptors where individual candidate amino acids had been exchanged between the human and rat GLP-1Rs identified a single residue that explained species selectivity of non-peptide binding. Replacement of tryptophane 33 in the human GLP-1R by serine (the homologous amino acid in the rat GLP-1R) resulted in a 100-fold loss of T-0632 affinity, whereas the converse mutation in the rat GLP-1R led to a reciprocal gain-of-function phenotype. These observations suggest that in a class B receptor, important determinants of non-peptide affinity reside within the extracellular amino-terminal domain. Compound T-0632 may mimic, and thereby interfere with, the putative ‘pseudo-tethering’ mechanism by which the amino terminus of class B receptors initiates the binding of cognate hormones.


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