Fig. 3: Thermodynamic rescue of V2R variants.
From: A small molecule stabilizer rescues the surface expression of nearly all missense variants in a GPCR
a, Well-folded receptors are properly trafficked to the membrane, but folding-defective variants are not properly trafficked. These experiments seek to test which variants can be rescued by thermodynamic rescue. b, Multiplexed score distribution for surface expression of all missense variants in control (37 °C) and rescue (27 °C) conditions. c, Comparison of all missense variants in control and rescue conditions. d, The relationship between free energy change and surface expression. The relationship between these two values is sigmoidal, meaning that the same free energy change (for example, that conferred by reducing culture temperature from 37 °C to 27 °C) can have effects of different magnitude on surface expression. e, The strategy used to identify sites with higher or lower levels of rescue than expected. A LOWESS curve is fit to the control versus rescue data; residuals to this line are calculated for all variants; positions with biased residuals are identified. f, Control versus rescue surface expression; LOWESS fit in solid black; the dashed x = y line is shown. g, Volcano plot comparing the average residual of all positions with the FDR adjusted (FDR = 0.1); –log10(P) was derived from Mann–Whitney U tests comparing the variant residuals at each position with all variant residuals at all other positions. The position with the most significantly different set of residuals is highlighted (W296). h, All missense variant effects at W296 are plotted with the whole population of missense variants in the background. Error bars represent the s.e.m.
