Fig. 4: S597 activates IR mutants that cause severe insulin resistance syndromes.

a Overall view of IR (gray)/insulin (orange) complex in a compact T-shape. The IR mutations we tested are indicated by red space-filling. b Overall view of IR (gray)/S597 (orange) complex in extended T-shape. The IR mutations we tested are indicated by red space-filling, except for E697, as we were not able to observe the α-CT in the IR/S597 complex. c Auto-phosphorylation of IR by the indicated concentrations of insulin or S597 for 10 min in 293FT cells expressing IR wild-type (WT) or indicated disease-causing mutants. d Quantification of the western blot data shown in c. Levels of pY IR were normalized to total IR levels and shown as intensities relative to that of IR WT in 10 nM insulin-treated cells. Mean ± SD. Each experiment was repeated three times. Significance calculated using two-tailed Student’s t-test; *p < 0.05, **p < 0.01, and ***p < 0.001. The exact p values are provided in the source data. e Auto-phosphorylation of IR by 10 nM insulin or S597 for 10 min in 293FT cells expressing IR WT or indicated disease-causing mutants. f Quantification of the western blot data shown in e. Levels of pY IR were normalized to total IR levels and shown as intensities relative to that of IR WT in insulin-treated cells. Mean ± SD. Each experiment was repeated three times. Significance calculated using two-tailed Student’s t-test; **p < 0.01 and ****p < 0.0001. The exact p values are provided in the source data. Source data are provided as a Source Data file.