Intrinsically unstructured proteins: Potential targets for drug discovery

Abstract

Problem statement: The function of a protein is dependent on its three-dimensional structure. However, numerous proteins lacking intrinsic globular 3D structure under physiological conditions had been recognized. These proteins are frequently involved in some of the most critical cellular control mechanisms and it appears that their rapid turnover, aided by their unstructured nature in the unbound state, provides a level of control that allows rapid and accurate responses of the cell to changing environmental conditions. Approach: A significant number of proteins known to be involved in protein deposition disorders were now considered to Be Intrinsically Unstructured Proteins (IUPs). For example, Aβ peptide and tau protein in Alzheimer's disease, PrP in Prion's disease and α-Synuclein in Parkinson's disease. The disorder of intrinsically unstructured proteins (IUP's) was crucial to their functions. They may adopt defined but extended structures when bound to cognate ligands. Their amino acid compositions were less hydrophobic than those of soluble proteins. They lack hydrophobic cores and hence did not become insoluble when heated. About 40% of eukaryotic proteins had at least one long (>50 residues) disordered region. Roughly 10% of proteins in various genomes had been predicted to be fully disordered. Presently over 100 IUP's had been identified; none are enzymes. Obviously, IUP's were greatly underrepresented in the Protein Data Bank, although there were few cases of an IUP bound to a folded (intrinsically structured) protein. Results: The five functional categories for intrinsically unstructured proteins and domains were entropic chains (bristles to ensure spacing, springs, flexible spacers/linkers), effectors (inhibitors and disassemblers), scavengers, assemblers and display sites. These IUPs could serve as potential targets for Structure Based Drug Design (SBDD) which stress on the transition from disordered to ordered confirmation through drug stimulation. Recently an unstructured domain of a regulatory protein had been found to be involved in inhibiting catalytic activity of insulin receptor and targeting this IUP would provide a new approach which can be employed in modifying insulin signaling in treatment of diabetes. IUPs were also involved diseases and disorders such as cardio vascular diseases, cancers and autoimmune disorders. Unstructured proteins had also been shown to be important components of invasion, survival and disguising strategies of pathogens such as Plasmodium falciparum. Conclusion: New greater focuses on proteins that were in some way unstructured normally would promise to provide a greater understanding of protein function particularly with respect to protein-protein interactions and hence can give new potential targets for future strategies. © 2009 Science Publications.