Fig. 7: Impact of the I777M substitution on PI3Ki binding.
From: Functional impact and molecular binding modes of drugs that target the PI3K isoform p110δ
Representative structures were derived from MD simulations. a ZSTK474 accommodation in the binding cleft between the N-lobe (dark gray) and C-lobe (light gray) of the p110δ-wt kinase domain. The contact area is indicated by blue surface color and prominent residues are emphasized by stick presentation in the zoom-in. b Conformational changes induced by the I777M mutation affect ZSTK474 binding. The difluoromethyl group of ZSTK474 fits between residues I777 and K779 (gray mesh) of p110δ-wt, but not between M777 and K779 of mutant p110δ (red mesh). The color of the mesh around M777 indicates sterically hindered (red) or undisturbed (gray) inhibitor binding. Moreover, the I777M substitution reduces the size of the binding pocket (red), from which the ZSTK474 molecule is expelled. c Different molecular interaction of idelalisib, ZSTK474 and copanlisib with p110δ-I777M. In the bar plots on the top, binding pocket residues are arranged from N to C terminus and assigned to regions of the specificity pocket (yellow), adenine and affinity pocket (blue), excluding an extended hinge region (gray), as well as catalytic and activation loop (purple). The height of each bar represents the total number of frames where the corresponding residue was found within a 3 Å distance to the inhibitors out of 1000 from each simulation. Only residues found in more than 75% of the frames are shown. The residues displayed in the bottom panel correspond to those shown in the top panel and are located within the binding pocket of individual inhibitors. Each residue is assigned a region-specific color according to the bar plots. The inhibitors are represented as balls and sticks and the residues as lines. Of note, the enzyme ligand structures show disturbed interactions with idelalisib and ZSTK474 in contrast to copanlisib binding, that is not subject to mutation-mediated resistance. For these three PI3Ki, the residues within a 3 Å distance illustrate interaction with different binding pocket regions.
