Potential Conformational Heterogeneity of p53 Bound to S100B(ββ)

McDowell, Chester; Chen, Jianlin; Chen, Jianhan

doi:10.1016/j.jmb.2013.01.001

Cited by 23 publications

(27 citation statements)

References 59 publications

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“…McDowell et al performed extensive atomistic simulations of the S100B ββ -bound conformation of p53 negative regulatory domain (NRD) in explicit solvent (with 1.0 μs total effective sampling) 67 . In agreement with earlier NMR studies, this analysis revealed that p53-NRD preserves significant flexibility when bound to S100B ββ , providing an atomistic description of this important fuzzy complex 67 …”

Section: Methods For the Idp/idpr Analysismentioning

confidence: 64%

Digested disorder

Uversky

2013

Intrinsically Disordered Proteins

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The current literature on intrinsically disordered proteins is blooming. A simple PubMed search for “intrinsically disordered protein OR natively unfolded protein” returns about 1,800 hits (as of June 17, 2013), with many papers published quite recently. To keep interested readers up to speed with this literature, we are starting a “Digested Disorder” project, which will encompass a series of reader’s digest type of publications aiming at the objective representation of the research papers and reviews on intrinsically disordered proteins. The only two criteria for inclusion in this digest are the publication date (a paper should be published within the covered time frame) and topic (a paper should be dedicated to any aspect of protein intrinsic disorder). The current digest covers papers published during the period of January, February and March of 2013. The papers are grouped hierarchically by topics they cover, and for each of the included paper a short description is given on its major findings.

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Section: Methods For the Idp/idpr Analysismentioning

confidence: 64%

Digested disorder

Uversky

2013

Intrinsically Disordered Proteins

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“…74 In particular, a centrally located Phe residue was found to interact strongly with the S100B peptide-binding pocket, while flanking segments were substantially disordered. McDowell et al, 73 by using two different state-of-the-art explicit water molecular dynamics force fields, confirmed the dynamic nature of this complex. Importantly, these authors also demonstrated that the obtained dynamic ensembles representing the bound state were consistent with the experimentally derived intermolecular NOE nuclear Overhauser effect (NOE) distance restraints for this complex.…”

mentioning

confidence: 87%

“…It should be pointed out that most assigned NOEs are extremely weak for the p53-NRD/S100B complex. Nonetheless, these results 73,74 emphasize the importance of considering potential disorder in protein structure calculations and that neglecting this possibility can lead to structural models that are too ordered.…”

mentioning

confidence: 94%

“…72 Fuzzy complexes may turn out to be more widespread than currently thought. This possibility is illustrated by computational studies 73,74 of the interaction between the calcium-regulated protein S100B and the disordered negative regulatory domain of p53 (p53-NRD), including a study 74 from the author's group. Previous NMR studies have suggested that the p53-NRD folds into a well-organized α-helix upon binding to S100B.…”

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confidence: 99%

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Intrinsically disordered proteins: structural and functional dynamics

Wallin¹

2017

RRB

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Abstract:The classical view holds that proteins fold into essentially unique three-dimensional structures before becoming biologically active. However, studies over the last several years have provided broad and convincing evidence that some proteins do not adopt a single structure and yet are fully functional. These intrinsically disordered proteins (IDPs) have been found to be highly prevalent in many genomes, including human, and play key roles in central cellular processes, such as regulation of transcription and translation, cell cycle, and cell signaling. Moreover, IDPs are overrepresented among proteins implicated in disease, including various cancers and neurodegenerative disorders. Intense efforts, by using both experimental and computational approaches, are consequently under way to uncover the molecular mechanisms that underpin the roles of IDPs in biology and disease. This review provides an introduction to the general biophysical properties of IDPs and discusses some of the recent emerging areas in IDP research, including the roles of IDPs in allosteric regulation, regulatory unfolding, and formation of intracellular membrane-less organelles. In addition, recent attempts at therapeutic targeting of IDPs by small molecules, noting in particular that IDPs represent a potentially important source of new drug targets in light of their central role in protein-protein interaction networks, are also reviewed.

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“…Disordered peptide segments, often found within longer regions of disorder in proteins, typically undergo a binding-induced folding transition upon contact with a target molecule such that a specific structure is assumed [1]. It is not uncommon, however, that significant conformational diversity persists even after binding [2]–[4]. Disordered regions in proteins play pivotal roles in controlling cellular signaling networks [5], protein subcellular localization [6], [7], protein degradation [8], and post-translational modification [9], [10].…”

Section: Introductionmentioning

confidence: 99%

Exploring Protein-Peptide Binding Specificity through Computational Peptide Screening

Bhattacherjee

Wallin

2013

PLoS Comput Biol

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The binding of short disordered peptide stretches to globular protein domains is important for a wide range of cellular processes, including signal transduction, protein transport, and immune response. The often promiscuous nature of these interactions and the conformational flexibility of the peptide chain, sometimes even when bound, make the binding specificity of this type of protein interaction a challenge to understand. Here we develop and test a Monte Carlo-based procedure for calculating protein-peptide binding thermodynamics for many sequences in a single run. The method explores both peptide sequence and conformational space simultaneously by simulating a joint probability distribution which, in particular, makes searching through peptide sequence space computationally efficient. To test our method, we apply it to 3 different peptide-binding protein domains and test its ability to capture the experimentally determined specificity profiles. Insight into the molecular underpinnings of the observed specificities is obtained by analyzing the peptide conformational ensembles of a large number of binding-competent sequences. We also explore the possibility of using our method to discover new peptide-binding pockets on protein structures.

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Potential Conformational Heterogeneity of p53 Bound to S100B(ββ)

Cited by 23 publications

References 59 publications

Digested disorder

Digested disorder

Intrinsically disordered proteins: structural and functional dynamics

Exploring Protein-Peptide Binding Specificity through Computational Peptide Screening

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