Structures of Pf20S and Hs20Sc β5 active sites with bound MPI-5 or bortezomib. Pf20S β5 (A and B) and Hs20S β5c (C and D) are shown as side (A and C) and top (B and D) views, with interacting residues (green) around the covalently bound MPI-5 (blue). (E and F) Cut-away showing solvent-accessible surface of the Pf20S β5 active site illustrating the different poses adopted by MPI-5 (E) and bortezomib (F). Substrate binding pockets, S1, S2, and S3 are marked. (G and H) Met22 creates a hydrophobic ledge over the ligand binding site in Pf20S β5, while Ala22 permits more solvent access in the Hs20S β5c active site around the covalently bound MPI-5. Pf20S β5 (I and J) and Hs20S β5c (K and L) are shown as side (I and K) and top (J and L) views ,with interacting residues (green) around the covalently bound bortezomib (blue).