Productive induced metastabilities in allosteric modulation of kinase function

MONTES DE OCA J.M.; RODRIGUEZ-FRIS A.; APPIGNANESI G.A.; FERNÁNDEZ A.S.

Villa Carlos Paz, Córdoba.

Congreso; XLII Reunión Anual de la Sociedad Argentina de Biofísica; 2013

Sociedad Argentina de Biofísica

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 since the binding site is not fit to a natural ligand (i.e. ATP or phosporylation substrate) of the protein. In this study, we elucidate the allosteric binding modality by unraveling 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 the association with the ligand. This productive induced metastability (PIM) is likely to translate into a general molecular design concept.