A potentiator of orthosteric ligand activity at GLP-1R acts via covalent modification

July 6th, 2014 by Whitney M Nolte

Nature Chemical Biology 10, 629 (2014). doi:10.1038/nchembio.1581

Authors: Whitney M Nolte, Jean-Philippe Fortin, Benjamin D Stevens, Gary E Aspnes, David A Griffith, Lise R Hoth, Roger B Ruggeri, Alan M Mathiowetz, Chris Limberakis, David Hepworth & Philip A Carpino

We report that 4-(3-(benzyloxy)phenyl)-2-ethylsulfinyl-6-(trifluoromethyl)pyrimidine (BETP), which behaves as a positive allosteric modulator at the glucagon-like peptide-1 receptor (GLP-1R), covalently modifies cysteines 347 and 438 in GLP-1R. C347, located in intracellular loop 3 of GLP-1R, is critical to the activity of BETP and a structurally distinct GLP-1R ago-allosteric modulator, N-(tert-butyl)-6,7-dichloro-3-(methylsulfonyl)quinoxalin-2-amine. We further show that substitution of cysteine for phenylalanine 345 in the glucagon receptor is sufficient to confer sensitivity to BETP.

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