RESUMO
Allosteric modulators of kinase function are of considerable pharmacological interest as blockers or agonists of key cell-signaling pathways. They are gaining attention due to their purported higher selectivity and efficacy relative to ATP-competitive ligands. Upon binding to the target protein, allosteric inhibitors promote a conformational change that purposely facilitates or hampers ATP binding. However, allosteric binding remains a matter of contention because the binding site does not fit with a natural ligand (i.e. ATP or phosphorylation substrate) of the protein. In this study, we show that allosteric binding occurs by means of a local structural motif that promotes association with the ligand. We specifically show that allosteric modulators promote a local metastable state that is stabilized upon association. The induced conformational change generates a local enrichment of the protein in the so-called dehydrons, which are solvent-exposed backbone hydrogen bonds. These structural deficiencies that are inherently sticky are not present in the apo form and constitute a local metastable state that promotes association with the ligand. This productive induced metastability (PIM) is likely to translate into a general molecular design concept.