Allosteric regulation: From Lumry and Eyring to the novel concept of Productive Induced Metastabilty (PIM).

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

Caxambu, Minas Gerais.

Congreso; XXIX Reunião Anual da FeSBE.; 2014

Federação de Sociedades de Biologia Experimental (FeSBE)

Already in the middle of the last century, Lumry R., Eyring, Biltonen and others reported that allosteric signaling is an activated process that requires the presence of structural or mobile defects to change the free energy of the protein and promote the ligated state. In particular, Lumry refers to the distortions of the H-bonds and local structures as the driving forces of "fluctuating enzymes"1,2. 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 dehydrons3, 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. In other words, we find that the allosterically activated conformation of the enzyme could not prevail in the ensemble of conformations of the Apo form of the enzyme because of the inherent instability of the packing defects (the Lumry "mobile defects"). Therefore the allosteric ligand acts protecting these exposed interaction from water, thus turning the active state into the most stable configuration. This productive induced metastability4 (PIM) is likely to translate into a general molecular design concept. 1. Lumry R & Eyring H (1954) Conformational changes in proteins, J. Phys. Chem. 58, 110-120. 2. Lumry, R., The new paradigm for protein research, in Gregory R B (ed.), Protein-solvent interactions, Marcel Dekker, Inc. New York (1995). 3. Fernández A, Transformative Concepts for Drug Design: Target Wrapping (Springer, Heidelberg, 2010). 4. Montes de Oca J., Rodriguez-Fris A., Appignanesi G. and Fernández A. Productive induced metastability in allosteric modulation of kinase function, FEBS J ,281, 3079?3091 (2014).