Fig. 2: Binding modes of SST-14 in SSTR2 and SSTR4.

a Side view of superimposition of SST-14-bound SSTR2 and SSTR4. SSTR2 and SSTR4 are shown as cartoon and colored in slate and pink, respectively. SST-14 is shown as cartoon and colored in orange and green, respectively. Disulfide bonds of SST-14 are shown as yellow sticks. b Extracellular view of structural superimposition of SST-14-bound SSTR2 and SSTR4. The rotation of the disulfide bond is indicated by red arrow. c Detailed interactions between the key pharmacophore (F7–W8–K9–T10) of SST-14 and SSTR2. Residues of SSTR2 are shown as slate sticks. Residues of SST-14 are shown as orange sticks. Polar interactions are indicated by red dash lines. d Detailed interactions between F6 and F11 of SST-14 and SSTR2. e Detailed interactions between the key pharmacophore (F7-W8-K9-T10) of SST-14 and SSTR4. Residues of SSTR4 are shown as pink sticks. Residues of SST-14 are shown as green sticks. f Detailed interactions between F6 and F11 of SST-14 and SSTR4. g, h Inhibition of forskolin-stimulated cAMP accumulation of WT SSTR2 and SSTR2 mutants (g) or WT SSTR4 and SSTR4 mutants (h) induced by SST-14 using HEK293F cells. The mutants are divided into two groups by dashed lines: (i) mutations of the residues that interact with the key pharmacophore (F7–W8–K9–T10) of SST-14; (ii) mutations of the residues that interact with F6 and F11 of SST-14. Bars represent the differences between the calculated SST-14 potency (pEC₅₀) of WT and mutants. Data are shown as means ± SEM from at least three independent experiments. One-way ANOVA was performed followed by Dunnett’s post-test and compared with WT. The P value was defined as: *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001. nd (not determined) indicates that a robust concentration response curve could not be determined within the concentration range tested. ^#Low surface expression level (< 40% of WT expression). Detailed statistical evaluation is shown in Supplementary information, Table S3.