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 function of many proteins is 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. Based on 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.

Elucidation of Ligand-Dependent Modulation of Disorder-Order Transitions in the Oncoprotein MDM2

“…Herbert et al discovered an allosteric inhibitor of FGFR that induces ordering of an unstructured segment into a helical region [ 8 ]. Similar mechanisms have been inferred for allosteric inhibitors of pyruvate kinase [ 9 ]. How to anticipate productive interactions in the context of rational drug design with experimental or computational methods remains however uncertain [ 10 ], and detailed investigations are necessary to progress our understanding of this molecular recognition mechanism.…”

Cancer/Testis Antigen PAGE4, a Regulator of c-Jun Transactivation, Is Phosphorylated by Homeodomain-Interacting Protein Kinase 1, a Component of the Stress-Response Pathway

“…As mentioned earlier, the overwhelming majority of CTAs are predicted to be intrinsically disordered as well as extensively modified by phosphorylation . In fact, the same is also true for IDPs in general − suggesting that this covalent modification plays an important role in the function of these proteins that typically transition from disorder to order when they interact with a target , or by altering spontaneous conformational behaviors. , However, in some IDPs, disorder may play an important functional role without evident disorder to order transition, − and in others, ordered regions within proteins that are not completely intrinsically disordered can also undergo regulated unfolding (transition to disorder). , Finally, disordered regions also have regulatory roles such as an ability to induce local unfolding within adjacent structured domains and hence facilitate allosteric communication between structured domains . In terms of structural consequences of site-specific phosphorylation, both disorder-to-order and order-to-disorder conformational transitions have been observed to follow phosphorylation. , However, the contribution of phosphorylation of disordered regions in IDP dynamics has not been critically evaluated in the majority of cases.…”

“… 55 , 56 However, in some IDPs, disorder may play an important functional role without evident disorder to order transition, 57 − 60 and in others, ordered regions within proteins that are not completely intrinsically disordered can also undergo regulated unfolding (transition to disorder). 61 , 62 Finally, disordered regions also have regulatory roles such as an ability to induce local unfolding within adjacent structured domains and hence facilitate allosteric communication between structured domains. 63 In terms of structural consequences of site-specific phosphorylation, both disorder-to-order and order-to-disorder conformational transitions have been observed to follow phosphorylation.…”