It's ok to be outnumbered - sub-stoichiometric modulation of homomeric protein complexes

An arsenal of molecular tools with increasingly diversified mechanisms of action is being developed by the scientific community to enable biological interrogation and pharmaceutical modulation of targets and pathways of ever increasing complexity. While most small molecules interact with the target of interest in a 1 : 1 relationship, a noteworthy number of recent examples were reported to bind in a sub-stoichiometric manner to a homomeric protein complex. This approach requires molecular understanding of the physiologically relevant protein assemblies and in-depth characterization of the compound's mechanism of action. The recent literature examples summarized here were selected to illustrate methods used to identify and characterize molecules with such mechanisms. The concept of one small molecule targeting a homomeric protein assembly is not new but the subject deserves renewed inspection in light of emerging technologies and increasingly diverse target biology, to ensure relevant in vitro systems are used and valuable compounds with potentially novel sub-stoichiometric mechanisms of action aren't overlooked. Recent literature examples of small molecules reported to modulate a homomeric protein complex at sub-stoichiometric concentrations were selected to discuss implications on drug discovery efforts.