The DynaMine webserver: predicting protein dynamics from sequence

Cilia, Elisa; Pancsa, Rita; Tompa, Péter; Lenaerts, Tom; Vranken, Wim

doi:10.1093/nar/gku270

Cited by 136 publications

(137 citation statements)

References 27 publications

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“…Order probability values span from 0, representing a highly dynamic protein residue, to 1, indicating a complete local stability. DynaMine2425 was used to predict the S 2 order parameter (Fig. 3B, black line) for backbone N-H groups, which gives an estimate of likelihood of the protein chain flexibility.…”

Section: Resultsmentioning

confidence: 99%

Identification of a Drug Targeting an Intrinsically Disordered Protein Involved in Pancreatic Adenocarcinoma

Neira

Bintz

Arruebo

et al. 2017

Sci Rep

106

138

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Intrinsically disordered proteins (IDPs) are prevalent in eukaryotes, performing signaling and regulatory functions. Often associated with human diseases, they constitute drug-development targets. NUPR1 is a multifunctional IDP, over-expressed and involved in pancreatic ductal adenocarcinoma (PDAC) development. By screening 1120 FDA-approved compounds, fifteen candidates were selected, and their interactions with NUPR1 were characterized by experimental and simulation techniques. The protein remained disordered upon binding to all fifteen candidates. These compounds were tested in PDAC-derived cell-based assays, and all induced cell-growth arrest and senescence, reduced cell migration, and decreased chemoresistance, mimicking NUPR1-deficiency. The most effective compound completely arrested tumor development in vivo on xenografted PDAC-derived cells in mice. Besides reporting the discovery of a compound targeting an intact IDP and specifically active against PDAC, our study proves the possibility to target the ‘fuzzy’ interface of a protein that remains disordered upon binding to its natural biological partners or to selected drugs.

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Section: Resultsmentioning

confidence: 99%

Identification of a Drug Targeting an Intrinsically Disordered Protein Involved in Pancreatic Adenocarcinoma

Neira

Bintz

Arruebo

et al. 2017

Sci Rep

106

138

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“…Disorder prediction was performed using default settings with DISOPRED2 (42), IUpred (43), Pondr-fit (44), and DynaMine (45). Protein sequence alignment was performed with ClustalW (46).…”

Section: Methodsmentioning

confidence: 99%

Rapid Proteasomal Degradation of Posttranscriptional Regulators of the TIS11/Tristetraprolin Family Is Induced by an Intrinsically Unstructured Region Independently of Ubiquitination

Ngoc

Wauquier

Soin

et al. 2014

Molecular and Cellular Biology

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The TIS11/tristetraprolin (TTP) CCCH tandem zinc finger proteins are major effectors in the destabilization of mRNAs bearing AU-rich elements (ARE) in their 3= untranslated regions. In this report, we demonstrate that the Drosophila melanogaster dTIS11 protein is short-lived due to its rapid ubiquitin-independent degradation by the proteasome. Our data indicate that this mechanism is tightly associated with the intrinsically unstructured, disordered N-and C-terminal domains of the protein. Furthermore, we show that TTP, the mammalian TIS11/TTP protein prototype, shares the same three-dimensional characteristics and is degraded by the same proteolytic pathway as dTIS11, thereby indicating that this mechanism has been conserved across evolution. Finally, we observed a phosphorylation-dependent inhibition of dTIS11 and TTP degradation by the proteasome in vitro, raising the possibility that such modifications directly affect proteasomal recognition for these proteins. As a group, RNAbinding proteins (RNA-BPs) have been described as enriched in intrinsically disordered regions, thus raising the possibility that the mechanism that we uncovered for TIS11/TTP turnover is widespread among other RNA-BPs.

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“…4 Coarsegrained descriptions of protein dynamics using elastic network models have been developed for the prediction of protein dynamics from average 3D structures. 5 Other approaches have been developed to predict protein dynamics and disorder based on protein sequences, [6][7][8][9][10][11][12][13] local densities, 14 atomic contacts, [15][16] and structural prototypes, 17 or other physical-chemical parameters, including chemical shifts. 18 With the exception of 4 MD, these approaches focus on classifying dynamics according to the magnitude of dynamics fluctuations independent of the underlying timescales.…”

Section: Introductionmentioning

confidence: 99%

Decoding the Mobility and Time Scales of Protein Loops

Brüschweiler

2015

J. Chem. Theory Comput.

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The flexible nature of protein loops and the time scales of their dynamics are critical for many biologically important events at the molecular level, such as protein interaction and recognition processes. In order to obtain a predictive understanding of the dynamic properties of loops, 500 ns molecular dynamics (MD) computer simulations of 38 different proteins were performed and validated using NMR chemical shifts. A total of 169 loops were analyzed and classified into three types, namely fast loops with correlation times <10 ns, slow loops with correlation times between 10 and 500 ns, and loops that are static over the course of the whole trajectory. Chemical and biophysical loop descriptors, such as amino-acid sequence, average 3D structure, charge distribution, hydrophobicity, and local contacts were used to develop and parametrize the ToeLoop algorithm for the prediction of the flexibility and motional time scale of every protein loop, which is also implemented as a public Web server (http://spin.ccic.ohio-state.edu/index.php/loop). The results demonstrate that loop dynamics with their time scales can be predicted rapidly with reasonable accuracy, which will allow the screening of average protein structures to help better understand the various roles loops can play in the context of protein-protein interactions and binding.

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The DynaMine webserver: predicting protein dynamics from sequence

Cited by 136 publications

References 27 publications

Identification of a Drug Targeting an Intrinsically Disordered Protein Involved in Pancreatic Adenocarcinoma

Identification of a Drug Targeting an Intrinsically Disordered Protein Involved in Pancreatic Adenocarcinoma

Rapid Proteasomal Degradation of Posttranscriptional Regulators of the TIS11/Tristetraprolin Family Is Induced by an Intrinsically Unstructured Region Independently of Ubiquitination

Decoding the Mobility and Time Scales of Protein Loops

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