Are all regions of folded proteins that undergo ligand-dependent order-disorder transitions targets for allosteric peptide mimetics?

Abstract

Although the classical view of how proteins function relied on well folded structures, it is now recognized that the functions of many proteins are dependent on being intrinsically disordered. The primary consideration in this work is the intermediate group of proteins that are overall well folded, but which contain small regions that undergo order-disorder transitions. In particular, the current focus is on those order-disorder transitions that are energetically coupled to ligand binding. As exemplified by the case of human liver pyruvate kinase (hL-PYK), peptides that mimic the sequence of the order-disorder region can be used as allosteric regulators of the enzyme. On the basis of this example and others reported in the literature, we propose that a similar use of peptides that mimic protein regions that experience ligand-dependent order-disorder transitions can be a generalized initiation point for the development of allosteric drugs.

Keywords: allosteric regulation; disordered regions; peptide mimetics; pyruvate kinase.

Figure 1

Based on 4IMA (28), the N-terminus of one subunit (black) crosses a subunit interface to interact with a second subunit (gray). The docking site for the first 17 residues has not yet been resolved. However, it appears that phosphorylation at Ser12 (denoted as P) results in the N-terminus transitioning from a bound ordered state to an unbound disordered state. Oxidation at Cys435 (spacefill on black subunit) also likely causes an order to disorder transition of the N-terminus (not shown), although it is likely that a larger region is interrupted by oxidation in comparison to the disorder caused by phosphorylation (28). Only one full subunit (gray) and a portion of a second subunit (black) of the homotetramer are included here.