Fig. 4: Cocrystal structures confirm A20 displacement and inform lead compound design.
From: Designing small molecules targeting a cryptic RNA binding site through base displacement
a, Representative MD starting states of the env8–CNCbl and env8–Cbl 4 complexes from one (of three) independent 1-µs trajectory. The A20(C6)–G19(C6) and A20(C6)–A68(N7) distances are shown as double arrows. In all structural representations, the binding-pocket nucleotides G19 (yellow), A20 (green) and A68 (cyan) are numbered in reference to full-length env8 and colored, the β-axial group is shown in magenta and dashed lines represent proposed hydrogen bonds. b, The average A20(C6)–G19(C6) (left) and A20(C6)–A68(N7) (right) distances measured over the course of three independent MD trajectories for both env8–CNCbl and env8–Cbl 4 complexes. c, Cocrystal structure of env2–CNCbl showing only the binding-pocket nucleotides and the β-axial group. All mesh representations correspond to a simulated annealing 2Fo − Fc map where A20 and the ligand were omitted from the model and are shown at 1σ contour. d, Same as c but for env2–Cbl 4. e, Same as c but for env2–Cbl 32 (left), along with a van der Waals sphere representation of the binding pocket (right). f, Same as e but for env2–Cbl 29. g, Same as c but for env2–Cbl 42. h, Schematic representation of design hypotheses that emerge from our 11 RNA–ligand cocrystal structures.
