Drug development and the cellular quality control system

Proteins serve in cellular roles that necessitate structural precision, a requirement overseen by the cellular quality control system (QCS). By rejecting misfolded proteins, the QCS protects against aberrant activity. Misfolding and subsequent retention by the QCS results in proteins that might maintain function but become misrouted and cause disease. Correcting the misrouting of misfolded mutant proteins often restores activity and addresses the underlying disease. Because of its small size, the gonadotropin-releasing hormone receptor has been an excellent model for G-protein-coupled receptor trafficking and has recently enabled elucidation of both the requirements to pass the QCS and the biochemical mechanism of rescue by pharmacological chaperones; this information will now enable rational design of these therapeutic agents. Here, we summarize what is known about the relation between receptor structure and interactions with the QCS with a view toward therapeutic development based on the rescue of misfolded and, consequently, misrouted mutants with drugs.