Abstract
Intrinsically disordered proteins (IDPs) are proteins that usually do not adopt well-defined native structures when isolated in solution under physiological conditions. Numerous IDPs have close relationships with human diseases such as tumor, Parkinson disease, Alzheimer disease, diabetes, and so on. These disease-associated IDPs commonly play principal roles in the disease-associated protein-protein interaction networks. Most of them in the disease datasets have more interactants and hence the size of the disease-associated IDPs interaction network is simultaneously increased. For example, the tumor suppressor protein p53 is an intrinsically disordered protein and also a hub protein in the p53 interaction network; α-synuclein, an intrinsically disordered protein involved in Parkinson diseases, is also a hub of the protein network. The disease-associated IDPs may provide potential targets for drugs modulating protein-protein interaction networks. Therefore, novel strategies for drug discovery based on IDPs are in the ascendant. It is dependent on the features of IDPs to develop the novel strategies. It is found out that IDPs have unique structural features such as high flexibility and random coil-like conformations which enable them to participate in both the “one to many” and “many to one” interaction. Accordingly, in order to promote novel strategies for drug discovery, it is essential that more and more features of IDPs are revealed by experimental and computing methods.
Highlights
According to the traditional sequence-to-structure-to-function paradigm, active proteins have well-defined three-dimensional structures under physiological conditions
We review characteristics of intrinsically disordered proteins (IDPs) and highlight the novel strategies for drug discovery based on the updated research of IDPs
The N-terminal (1~39) of p53 (p531–39) has been proved to be intrinsically disordered [10], but the content of leucine is up to 15.4% [11], which is thought to be an order-promoting amino acid and the statistical frequency value in disordered proteins is 5.44% [12], Leucine plays an essential role in the formation of hydrophobic cluster and the leucine-rich hydrophobic cluster promotes the formation of a collapsed structure of p531–39 [11]
Summary
According to the traditional sequence-to-structure-to-function paradigm, active proteins have well-defined three-dimensional structures under physiological conditions. 1990s, it was reported that there is another class of proteins, which have no well-defined structures under physiological conditions, but still have biological functions [1,2]. These proteins with intrinsically disordered regions (IDRs) are called intrinsically disordered proteins (IDPs). The functional repertoire of IDPs complements the functions of ordered proteins. IDPs have brought great challenges to the classical structural and functional relationship of proteins, which is a new opportunity to reveal the essential relationship especially for these types of disordered proteins. In order to make full use of IDPs for drug discovery, it is important to study the characters of sequence, structure, dynamics, biophysics and protein-protein interaction network of these proteins.
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