Residues with variable roles in pocket formation in apo structures may indicate cryptic binding sites. Analyses of apo structures of IL-2 superfamily members and a set of simulated conformers of apo IL-2 show that residues that have variable roles in pocket formation include those that undergo the significant side-chain conformational rearrangements necessary to accommodate small molecule interface inhibitors. (A) Residues that are pocket-lining in a small proportion of the 17 apo homologues of IL-2 are highlighted on the IL-2 surface (dark blue represents the median Provar score of 0.26, with lighter blues indicating a higher or lower score). A region to the left of the α receptor interface (c.f. Figure 9A) is prominent in this visualisation and indicates structural heterogeneity of this region across the superfamily. (B) An expanded ribbon view of that part of this region of apo IL-2 coloured as in (A). Side-chains of surface residues in this region are shown in stick representation, superimposed are side chain conformations (cyan) in an inhibitor bound state [PDB:1M48]. The pocket in which the inhibitor binds is not present in the IL-2 crystal structure and large movements of side chains of Arg 38, Lys 35, Met 39, Phe 42 and Leu 72 enable ligand binding. The majority of these residues have pocket forming roles in some structural homologues. (C) A ribbon view showing the same region as (B) coloured to highlight residues that show variable roles in pocket formation in tCONCOORD simulations of apo IL-2 (dark blue represents the median Provar score of 0.31). The pocket-forming capability of Phe 42 and Arg 38, required for inhibitor binding, is shown by Provar analyses of these IL-2 simulations.