Back to the Future: Nuclear Magnetic Resonance and Bioinformatics Studies on Intrinsically Disordered Proteins

Dunker, A. Keith; Oldfield, Christopher J.

doi:10.1007/978-3-319-20164-1_1

Cited by 19 publications

(17 citation statements)

References 169 publications

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“…In the case of disordered proteins, however, dynamical regions generally appear as missing electron density [110–113]. Therefore, solution-state techniques that do not require crystallization, such as nuclear magnetic resonance (NMR) spectroscopy and other techniques described here (Table 1), coupled within integrative structural biology methods (Table 1) are better suited to probe disordered proteins, as they can directly characterize their conformational heterogeneity.…”

Section: Methods Of Characterizing Ligand Interactions With Monomericmentioning

confidence: 99%

Methods of probing the interactions between small molecules and disordered proteins

Heller

Aprile

Vendruscolo

2017

Cell. Mol. Life Sci.

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It is generally recognized that a large fraction of the human proteome is made up of proteins that remain disordered in their native states. Despite the fact that such proteins play key biological roles and are involved in many major human diseases, they still represent challenging targets for drug discovery. A major bottleneck for the identification of compounds capable of interacting with these proteins and modulating their disease-promoting behaviour is the development of effective techniques to probe such interactions. The difficulties in carrying out binding measurements have resulted in a poor understanding of the mechanisms underlying these interactions. In order to facilitate further methodological advances, here we review the most commonly used techniques to probe three types of interactions involving small molecules: (1) those that disrupt functional interactions between disordered proteins; (2) those that inhibit the aberrant aggregation of disordered proteins, and (3) those that lead to binding disordered proteins in their monomeric states. In discussing these techniques, we also point out directions for future developments.

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Section: Methods Of Characterizing Ligand Interactions With Monomericmentioning

confidence: 99%

Methods of probing the interactions between small molecules and disordered proteins

Heller

Aprile

Vendruscolo

2017

Cell. Mol. Life Sci.

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“…Recently, Dunker and Oldfield 111 suggested that the interaction between an IDP/IDR and its partner should not be described as induced fit where the protein is folded but can adjust its structure to fit the substrate. However, since the discovery of IDPs/IDRs, the sequence-structure paradigm has been revolutionized.…”

Section: Conformational Selection Induced Fit and Beyondmentioning

confidence: 99%

Features of molecular recognition of intrinsically disordered proteins via coupled folding and binding

et al. 2019

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The sequence–structure–function paradigm of proteins has been revolutionized by the discovery of intrinsically disordered proteins (IDPs) or intrinsically disordered regions (IDRs). In contrast to traditional ordered proteins, IDPs/IDRs are unstructured under physiological conditions. The absence of well‐defined three‐dimensional structures in the free state of IDPs/IDRs is fundamental to their function. Folding upon binding is an important mode of molecular recognition for IDPs/IDRs. While great efforts have been devoted to investigating the complex structures and binding kinetics and affinities, our knowledge on the binding mechanisms of IDPs/IDRs remains very limited. Here, we review recent advances on the binding mechanisms of IDPs/IDRs. The structures and kinetic parameters of IDPs/IDRs can vary greatly, and the binding mechanisms can be highly dependent on the structural properties of IDPs/IDRs. IDPs/IDRs can employ various combinations of conformational selection and induced fit in a binding process, which can be templated by the target and/or encoded by the IDP/IDR. Further studies should provide deeper insights into the molecular recognition of IDPs/IDRs and enable the rational design of IDP/IDR binding mechanisms in the future.

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“…The relative merits of the three main structural methods for assessing protein stability are shown in Table 2. Given the solid-state nature of protein crystallography it is often difficult to crystallize dynamic and disordered proteins, and for this reason NMR spectroscopy has been one of the main tools used to study IDPs such as p53 and CREB (Brutscher et al, 2015;Dunker & Oldfield, 2015;Mujtaba et al, 2004;Fig. 2d).…”

Section: Key Techniques For Determining Protein Stabilitymentioning

confidence: 99%

Protein stability: a crystallographer's perspective

Deller

Kong

Rupp

2016

Acta Crystallogr F Struct Biol Commun

212

137

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Protein stability is a topic of major interest for the biotechnology, pharmaceutical and food industries, in addition to being a daily consideration for academic researchers studying proteins. An understanding of protein stability is essential for optimizing the expression, purification, formulation, storage and structural studies of proteins. In this review, discussion will focus on factors affecting protein stability, on a somewhat practical level, particularly from the view of a protein crystallographer. The differences between protein conformational stability and protein compositional stability will be discussed, along with a brief introduction to key methods useful for analyzing protein stability. Finally, tactics for addressing protein-stability issues during protein expression, purification and crystallization will be discussed.

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Back to the Future: Nuclear Magnetic Resonance and Bioinformatics Studies on Intrinsically Disordered Proteins

Cited by 19 publications

References 169 publications

Methods of probing the interactions between small molecules and disordered proteins

Methods of probing the interactions between small molecules and disordered proteins

Features of molecular recognition of intrinsically disordered proteins via coupled folding and binding

Protein stability: a crystallographer's perspective

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