*2.3. The Conservation Pattern (ABCG1, ABCG4), (ABCG2), (ABCG5), (ABCG8) Defines a Possible Allosteric Pathway in ABCG Proteins*

The pattern (ABCG1, ABCG4), (ABCG2), (ABCG5), (ABCG8) separates the proteins by their probable substrate interactions, and is the most populated set of functionally divergent columns, with 33 columns. Residues corresponding to these columns are mapped on to an ABCG2 structure in Figure 3a. In this structure of ABCG2 (and also observed if mapped onto ABCG5/G8, Supplementary Figure S2), these residues form a "corkscrew" pattern from the cytoplasmic face of the NBDs, through the TMDs to the extracellular face of the protein. This distribution implies that some important differences in the function of members the G subfamily are due to differences in allostery, as corresponding residues are ideally placed to form a network of residues coordinating conformational changes throughout the protein. Their distribution can be compared with residues with the conservation pattern (ABCG1, ABCG4), (ABCG2), (ABCG5, ABCG8) (Figure 3b) and the much less common pattern (ABCG1), (ABCG4), (ABCG2), (ABCG5), (ABCG8) (Figure 3c).

**Figure 3.** Functionally divergent residues shown on ABCG2 (PDBID: 6vxf) shown as coloured spheres on three views of the structure. (**a**) Residues conserved in the pattern (ABCG1, ABCG4), (ABCG2) (ABCG5), (ABCG8) as green spheres. (**b**) Residues conserved in the pattern (ABCG1, ABCG4), (ABCG2), (ABCG5, ABCG8) as pink spheres. (**c**) Residues conserved differently in each protein, i.e., with the conservation pattern (ABCG1), (ABCG4), (ABCG2), (ABCG5), (ABCG8) as purple spheres.
