Elucidation of the Hsp90 C-Terminal Inhibitor Binding Site

The only crystal structures of Hsp90's C-terminal domain are of the closed, clamped conformation which is unable to bind inhibitors. Matts and coworkers have been able to come up with a new model for the binding of C-terminal Hsp90 inhibitors, which is more consistent with prior biochemical studies than previous models. To elucidate how novobiocin (NB) binds the C terminal domain, they used a photolabile analog of NB to determine which residues were in the binding site. After that, they performed molecular modeling studies to gain a clearer understanding of how NB binds. Knowledge of the binding mode of these inhibitors should lead to development of more potent drugs which target the C-terminal binding site.