Fig. 5: Structural details of the DCAF1-WDR5-PROTAC interactions and their significance to PROTAC activity.

a PROTAC 1-3 bring DCAF1 and WDR5 together to form a ternary complex. The longer PROTAC 2 and 3 are compressed to a similar effective length as PROTAC 1 in the ternary structures. Surface representations also indicate diminishing contacts between WDR domains with increasing PROTAC linker length. DCAF1 and WDR5 are colored as in Fig. 4. b–d Interactions between the top side of the WDR domains of DCAF1 and WDR5 in ternary complex with PROTAC change depending on linker length. Hydrogen bonding and electrostatic interactions are shown as broken black lines. Hydrophobic/van der Waals interactions are shown as brown concave lines. In the presence of PROTAC 1 or 2, the DCAF1-WDR5 interaction is mediated by various hydrogen bonds (b, c), which disappear in the interface as the linker becomes longer. Weak hydrophobic/van der Waals interactions sustain the DCAF1-WDR5 interface in the presence of the longest PROTAC 3 (d). e–g PROTAC linkers of different lengths are accommodated inside the space formed by DCAF1 and WDR5 by compacting. e PROTAC 1 (orange sticks) assumes a fully extended configuration inside the pocket. A flexible loop, formed by DCAF1 residues 1313-1333, is retracted away from the PROTAC linker, resulting in an open cavity filled with water molecules. Only water molecules participating in hydrogen bonding with nearby solvent and/or protein residues are shown. f The longer PROTAC 2 linker is kinked inside the DCAF1-WDR5 interface. Notably, the flexible loop formed by DCAF1 residues 1313–1333 assumes a different configuration that cradles the curved portion of the linker. In addition, a rotamer shift for DCAF1’s W1156 occurs to complement linker shape. g The compacted linker of PROTAC 3, longer than those of PROTAC 1 and 2, engenders a new interaction pattern with protein residues. The longer linker is further compressed inside the binding space, resulting in a more curved configuration. The nearby loop of DCAF1 (residues 1313–1333, with residues 1315–1326 disordered and not modeled) is displaced from its original location in the PROTAC 1 and 2 ternary complexes.