Fig. 17
From: PROTAC’ing oncoproteins: targeted protein degradation for cancer therapy
(a) Crystal structure of BRD4BD2-compound 78-VHL ternary complex (PDB 6SIS). The binding pattern of 78 nearly superimposes that of MZ1 in complex with Brd4 and VHL (PDB ID: 5T35). Important interactions of this macrocyclic PROTAC include hydrogen bonding with VHL residues Y98, H110, S111, and H115 and BRD4 residues N433 and H437. A T-stacking π - π interaction with VHLY98 is also observed. (b) Crystal structure of BRD4BD1-Compound 87-VHL ternary complex (PDB 7KHH). The hydrophobic linker assumes a collapsed conformation to enable intramolecular hydrophobic interactions between the linker, the aryl rings, and the tertbutyl group. Interactions between the ligands and their respective proteins are depicted. Images created using Schrödinger Bioluminate with PDBs 6SIS and 7KHH. BRD4BD subunits are depicted in cyan and VHL in brownish orange