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Productive induced metastability in allosteric modulation of kinase function
Author(s) -
Montes de Oca Joan,
Rodriguez Fris Ariel,
Appignanesi Gustavo,
Fernández Ariel
Publication year - 2014
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.12844
Subject(s) - allosteric regulation , allosteric enzyme , chemistry , ligand (biochemistry) , biophysics , phosphorylation , plasma protein binding , binding site , conformational change , stereochemistry , receptor , biochemistry , biology
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.