Productive induced metastability in allosteric modulation of kinase function.
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.
Sección Fisicoquímica, INQUISUR-UNS-CONICET-Departamento de Química, Universidad Nacional del Sur, Bahía Blanca, Argentina.
Joan
J
Montes de Oca
Ariel
A
Rodriguez Fris
Gustavo
G
Appignanesi
Ariel
A
Fernández
D000494:Allosteric Regulation; D000495:Allosteric Site; D001051:Apoenzymes / Q000737:chemistry; D001549:Benzamides / Q000737:chemistry; D020134:Catalytic Domain; D003198:Computer Simulation; D004795:Enzyme Stability; D006801:Humans; D006860:Hydrogen Bonding; D000068877:Imatinib Mesylate; D008958:Models, Molecular; D010879:Piperazines / Q000737:chemistry; D047428:Protein Kinase Inhibitors / Q000737:chemistry; D011494:Protein Kinases / Q000737:chemistry*; D011743:Pyrimidines / Q000737:chemistry
D001051:Apoenzymes; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011494:Protein Kinases
allosteric drugs; allostery; binding; hydrogen bonds; kinases