Intrinsically Disordered Proteins as Regulators of Transient Biological Processes and as Untapped Drug Targets

Abstract

Intrinsically disordered proteins (IDPs) are critical players in the dynamic control of diverse cellular processes, and provide potential new drug targets because their dysregulation is closely related to many diseases. This review focuses on several medicinal studies that have identified low-molecular-weight inhibitors of IDPs. In addition, clinically relevant liquid–liquid phase separations—which critically involve both intermolecular interactions between IDPs and their posttranslational modification—are analyzed to understand the potential of IDPs as new drug targets.

Evidence for an Ordering Transition near 120 K in an Intrinsically Disordered Protein, Casein

“…It is worth noting in this respect that the disorder-to-order transition in IDPs is widely recognized as a common property of IDPs upon their interaction with a binding partner [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 34 ]. Data of neutron and light scattering techniques [ 37 ] show that β-casein partially folds and stiffens upon calcium binding, and that in the unfolded state it is softer than folded proteins—the features analogous to those observed here, with the difference that the transition here is induced by the temperature increase.…”

“…The protein functions are determined by their three-dimensional tertiary structures. However, there exist proteins possessing unstructured regions of significant size, being nevertheless biologically active; these proteins are called intrinsically disordered proteins (IDPs), as reviewed in [ 1 , 2 , 3 , 4 , 5 , 6 , 7 ]. IDPs carry out various functional roles, such as signal transduction and storage of small molecules.…”

“…An intriguing property of many IDPs is their ability to undergo disorder-to-order transitions upon target binding, when specific recognition protein residues adopt secondary or tertiary structural elements upon interaction with a binding partner [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 ]. These transitions contribute to protein function by facilitating the binding process and accelerating biochemical reactions.…”

Deep learning in prediction of intrinsic disorder in proteins

“…Numerous studies of IDPs reveal that they are crucial for a wide spectrum of cellular functions that include signaling, molecular recognition and assembly, cell cycle regulation, transcription, translation and phase separation [10] , [11] , [12] , [13] , [14] , [15] , [16] , [17] , [18] , [19] . Moreover, given their functional importance and prevalence in the human diseasome [12] , [20] , [21] , [22] , they serve as promising and currently underutilized leads for rational drug design efforts [23] , [24] , [25] , [26] , [27] .…”

“…Computational predictors already made large impact on the intrinsic disorder field, by powering a rapid acceleration in the research on IDPs and IDRs [35] . They are also used across many areas including rational drug design [23] , [24] , [25] , [26] , structural genomics [36] , [37] , [38] , and medicine [39] , [40] .…”