Fig. 5

MD simulations reveal PPI interfaces between p38δ and VHL that vary between SJFδ and SJFα recruitment. a The SJFδ-recruited VHL interacts with p38δ in a different mode than the SJFα-recruited VHL. p38δ, VHL, and either SJFδ or SJFα were docked and a 100-ns MD simulation relaxed the ternary structure. The p38δ:SJFδ:VHL ternary complex is colored in tan and the p38δ:SJFα:VHL ternary complex is colored in dark blue. The p38δ structures from both ternary complex MD simulations were aligned and the resulting divergent VHL structures can be visualized. b SJFδ and SJFα PROTACs deviate at the exit of the p38δ kinase pocket to interact with the p38δ:VHL PPI interface in distinct ways. Using the same p38δ alignment as in (a), the p38δ and VHL structures were hidden such that individual PROTACs could be visualized in stick representation. SJFδ carbons are colored in tan and SJFα carbons are colored in dark blue with oxygen atoms colored in red, nitrogen atoms in blue, sulfur atoms in yellow, and fluorine atoms in pale blue for both PROTACs. SJFδ or SJFα (which are composed of the same foretinib warhead) show profound alignment within the p38δ kinase, but deviate greatly upon exiting the pocket. Linker length differences between SJFδ (10 atoms) and SJFα (13-atoms) reveal the limits in their respective ability to dock along the p38δ:VHL PPI interface. In addition, the orientation of attachment of the VHL-recruiting ligands result in hydroxyproline (Hyp) moieties that differ by ~147° between the two PROTAC structures