Abstract
Protein–protein interactions involving disordered partners have unique features and represent prominent targets in drug discovery processes. Intrinsically Disordered Proteins (IDPs) are involved in cellular regulation, signaling and control: they bind to multiple partners and these high-specificity/low-affinity interactions play crucial roles in many human diseases. Disordered regions, terminal tails and flexible linkers are particularly abundant in DNA-binding proteins and play crucial roles in the affinity and specificity of DNA recognizing processes. Protein complexes involving IDPs are short-lived and typically involve short amino acid stretches bearing few “hot spots”, thus the identification of molecules able to modulate them can produce important lead compounds: in this scenario peptides and/or peptidomimetics, deriving from structure-based, combinatorial or protein dissection approaches, can play a key role as hit compounds. Here, we propose a panoramic review of the structural features of IDPs and how they regulate molecular recognition mechanisms focusing attention on recently reported drug-design strategies in the field of IDPs.
Highlights
Protein–protein interactions involving disordered partners have unique features and represent prominent targets in drug discovery processes
The recent importance of Intrinsically disordered proteins (IDPs) and hybrid proteins, containing ordered and disordered regions (IDPRs), points out a key role for functional disorder in cell regulation and they are normally tightly controlled, rigorous investigations of IDP functions and dysfunctions led to the recognition that they are prevalent among disease-related proteins and that many human diseases are based on the inability of a protein region to adopt its functional conformational state, leading to protein misfolding, loss of biological activity, gain of toxic function and/or protein aggregation [17,18]
Ongoing studies are focused on the design of peptidomimetics able to stabilize G-quadruplex/NPM1 complex to be tested as potential therapeutics in the field of acute myeloid leukemia (AML) disease
Summary
Disordered proteins (IDPs) are not endowed with stable tertiary structures but are involved in recognition processes with other biomolecules (including proteins): during the formation of complexes the disordered protein regions simultaneously undergo to folding and binding events These regions are usually specific motifs, named molecular recognition features (MoRFs), bearing short sequences able to transit from disordered to partially ordered configurations following a fly-casting mechanism [1]. The most common use of disordered regions by hub proteins is to bind to multiple partners [13,15] even if there are several examples of linear interaction motifs with largely overlapping functional properties This mode is focused on distilling a short consensus sequence pattern from proteins with a common interaction partner. IDPs can bind to structured hub proteins and flexible linkers between functional domains enable mechanisms that facilitate binding diversity [12]
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