Skip to main content
Fig. 4 | Genome Biology

Fig. 4

From: A comprehensive map of human glucokinase variant activity

Fig. 4

Interpreting the glucokinase activity scores using analyses of evolutionary conservation and conformational free energies. A Plots showing the residue median activity scores and evolutionary conservation scores for GCK. For activity scores, a score of one corresponds to a wild-type-like activity, a score of zero corresponds to total loss of function, and a score above one indicates increased activity. For GEMME scores (ΔE score), a score of zero suggests compatibility with function, while a high negative score indicates that mutations are detrimental. B Plots showing the residue median of activity scores, ΔΔG of the super-open conformation, ΔΔG of the closed conformation, and the difference between the ΔΔG in the closed and super-open conformation (ΔΔGsuper-open – ΔΔGclosed, Δ(ΔΔG)), respectively. For ΔΔG of the super-open and closed conformations, a score of zero corresponds to the same stability as wild-type, while a high negative score means decreased stability compared to wild-type GCK. For Δ(ΔΔG), a score of zero indicates an equal destabilization of the two conformations. A negative score indicates a destabilization of the closed state relative to the super-open, while a positive score indicates a destabilization of the super-open conformation relative to the closed. Note that residues at positions 157–179 are absent from the structure of the super-open conformation, and therefore lack super-open ΔΔG and Δ(ΔΔG) scores. C The two GCK conformations colored by residue median Δ(ΔΔG). The 157–179 region is colored black in both structures. D Plot showing the ΔΔG values of seven previously characterized variants [22, 70]. The background coloring indicates whether the ΔΔG value is in the stable (green), intermediate (grey) or unstable (red) range. Variants that are predicted to shift the equilibrium towards the closed conformation will have the highest ΔΔG in the super-open state, and vice versa for variants that are predicted to shift the equilibrium towards the inactive state. PDBs: super-open (1V4T) and closed (1V4S)

Back to article page