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. Author manuscript; available in PMC: 2022 Mar 1.
Published in final edited form as: Biochem Pharmacol. 2021 Feb 3;185:114451. doi: 10.1016/j.bcp.2021.114451

Figure 8: Irreversible scaffold A acts likely via two distinct mechanisms:

Figure 8:

(A) Sequence alignment of SCTR and GLP-1R, specifically TM5, ICL3 and TM6 and highlighting homolog residues C347GLP−1R and K317SCTR; generated by GPCRdb. cAMP dose-response of (B, C, top panels) GLP-1, (B, C, bottom panels) GLP-1(9–36), Sec-FL (D, E, top panels) or Sec(3–27) (D, E, bottom panels) stimulating (B, C, left panels) GLP-1R-WT, (B, C, right panels) GLP-1R C347A, (D, E, left panels) SCTR WT, (D, E, middle panels) SCTR K317A or (D, E, right panels) SCTR K317C treated with DMSO (black), 12.5–25 μM of (B, D) BETP (purple) or 2-sulfonyl pyrimidines A1 (dark green), A2 (light green), A3 (light blue-green) or (C, E) 2-mercapto pyrimidines B1 (light blue), B2 (dark blue); TR-FRET ratios resulting from cAMP accumulation normalized to corresponding ligands; graphs plotted using GraphPad Prism; experiments performed in duplicate in at least three independent experiments; data points shown as mean ± SEM. Statistical significance for EC50 shifts determined using GraphPad Prism’s unpaired t-test corrected with Holm-Sidak method, α = 0.01; all results statistically significant (p < 0.01) if not indicated otherwise (ns = not significant).