NPDock: a web server for protein–nucleic acid docking

Tuszyńska, Irina; Magnus, Marcin; Jonak, Katarzyna; Dawson, Wayne; Bujnicki, Janusz

doi:10.1093/nar/gkv493

Cited by 208 publications

(146 citation statements)

References 32 publications

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“…We first established that nuclear-localized α-Syn binds to distinct DNA sequences in the chromatin and physically binds naked DNA in vitro . To gain further molecular insights into α-Syn’s DNA binding and nicking activity, we used MD simulation with nucleic acid-protein docking method (NPDock) [54] to predict the three-dimensional structure of the α-Syn-DNA complex (Fig. 9 and Supplementary Figure 3).…”

Section: Discussionmentioning

confidence: 99%

Chromatin-Bound Oxidized α-Synuclein Causes Strand Breaks in Neuronal Genomes in in vitro Models of Parkinson’s Disease

Vasquez

Mitra

Hegde

et al. 2017

JAD

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Alpha-synuclein (α-Syn) overexpression and misfolding/aggregation in degenerating dopaminergic neurons have long been implicated in Parkinson’s disease (PD). The neurotoxicity of α-Syn is enhanced by iron (Fe) and other pro-oxidant metals, leading to generation of reactive oxygen species in PD brain. Although α-Syn is predominantly localized in presynaptic nerve terminals, a small fraction exists in neuronal nuclei. However, the functional and/or pathological role of nuclear α-Syn is unclear. Following up on our earlier report that α-Syn directly binds DNA in vitro, here we confirm the nuclear localization and chromatin association of α-Syn in neurons using proximity ligation and chromatin immunoprecipitation analysis. Moderate (~2-fold) increase in α-Syn expression in neural lineage progenitor cells (NPC) derived from induced pluripotent human stem cells (iPSCs) or differentiated SHSY-5Y cells caused DNA strand breaks in the nuclear genome, which was further enhanced synergistically by Fe salts. Furthermore, α-Syn required nuclear localization for inducing genome damage as revealed by the effect of nucleus versus cytosol-specific mutants. Enhanced DNA damage by oxidized and misfolded/oligomeric α-Syn suggests that DNA nicking activity is mediated by the chemical nuclease activity of an oxidized peptide segment in the misfolded α-Syn. Consistent with this finding, a marked increase in Fe-dependent DNA breaks was observed in NPCs from a PD patient-derived iPSC line harboring triplication of the SNCA gene. Finally, α-Syn combined with Fe significantly promoted neuronal cell death. Together, these findings provide a novel molecular insight into the direct role of α-Syn in inducing neuronal genome damage, which could possibly contribute to neurodegeneration in PD.

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Section: Discussionmentioning

confidence: 99%

Chromatin-Bound Oxidized α-Synuclein Causes Strand Breaks in Neuronal Genomes in in vitro Models of Parkinson’s Disease

Vasquez

Mitra

Hegde

et al. 2017

JAD

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“…Discovery Studio 2.5 (Accelrys Inc., San Diego, CA) was used to prepare and apply CHARMm force field to DNA sequences and SMAD3 MH1 (PDB ID: 1MHD (6)) domain for modelling. Docking was performed in NP Dock server as described previously (25) with default docking parameters and RMSD threshold in the clustering procedure set to 5 Å. After refinement, best scored decoys from the three largest clusters were analyzed and the best pose (highest probability) was used to identify DNA-protein interactions using Discovery Studio software.…”

Section: Methodsmentioning

confidence: 99%

Transforming growth factor β suppresses peroxisome proliferator-activated receptor γ expression via both SMAD binding and novel TGF-β inhibitory elements

Lakshmi

Reddy

2017

Biochemical Journal

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Transforming growth factor β (TGF-β) contributes to wound healing and, when dysregulated, to pathological fibrosis. TGF-β and the anti-fibrotic nuclear hormone receptor peroxisome proliferator-activated receptor γ (PPARγ) repress each other’s expression, and such PPARγ downregulation is prominent in fibrosis and mediated, via previously unknown SMAD-signaling mechanisms. Here we show that TGF-β induces association of SMAD3 with both SMAD4, needed for translocation of the complex into the nucleus, and the essential context-sensitive corepressors E2F4 and p107. The complex mediates TGF-β-induced repression by binding to regulatory elements in the target promoter. In the PPARG promoter, we found that the SMAD3-SMAD4 complex binds both to a previously unknown consensus TGF-β inhibitory element (TIE) and also to canonical SMAD-binding elements (SBEs). Furthermore, the TIE and SBEs independently mediated partial repression of PPARG transcription, the first demonstration of a TIE and SBEs functioning within the same promoter. Also, TGF-β-treated fibroblasts contained SMAD complexes that activated a SMAD target gene in addition to those repressing PPARG transcription, the first finding of such dual activity within the same cell. These findings describe in detail novel mechanisms by which TGF-β represses PPARG transcription, thereby facilitating its own pro-fibrotic activity.

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“…The structure of the YbxF protein was predicted by fold-recognition using the GeneSilico metaserver (Kurowski and Bujnicki 2003), followed by template-based modeling using the L7Ae protein structure (PDB ID: 2FC3) as a template, with MODELLER (Sali and Blundell 1993). RNA-protein docking was performed using a procedure that in the meantime has been automated and now is available via the NPDock web server (Tuszynska et al 2015). The models turned out to be quite accurate (the best one had 3.99 Å RMSD to the reference structure).…”

Section: Puzzlementioning

confidence: 99%

RNA-Puzzles Round III: 3D RNA structure prediction of five riboswitches and one ribozyme

Miao

Adamiak

Antczak

et al. 2017

RNA

Self Cite

186

209

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RNA-Puzzles is a collective experiment in blind 3D RNA structure prediction. We report here a third round of RNA-Puzzles. Five puzzles, 4, 8, 12, 13, 14, all structures of riboswitch aptamers and puzzle 7, a ribozyme structure, are included in this round of the experiment. The riboswitch structures include biological binding sites for small molecules (S-adenosyl methionine, cyclic diadenosine monophosphate, 5-amino 4-imidazole carboxamide riboside 5 ′ -triphosphate, glutamine) and proteins (YbxF), and one set describes large conformational changes between ligand-free and ligand-bound states. The Varkud satellite ribozyme is the most recently solved structure of a known large ribozyme. All puzzles have established biological functions and require structural understanding to appreciate their molecular mechanisms. Through the use of fast-track experimental data, including multidimensional chemical mapping, and accurate prediction of RNA secondary structure, a large portion of the contacts in 3D have been predicted correctly leading to similar topologies for the top ranking predictions. Template-based and homologyderived predictions could predict structures to particularly high accuracies. However, achieving biological insights from de novo prediction of RNA 3D structures still depends on the size and complexity of the RNA. Blind computational predictions of RNA structures already appear to provide useful structural information in many cases. Similar to the previous RNA-Puzzles Round II experiment, the prediction of non-Watson-Crick interactions and the observed high atomic clash scores reveal a notable need for an algorithm of improvement. All prediction models and assessment results are available at http://ahsoka.ustrasbg.fr/rnapuzzles/.

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NPDock: a web server for protein–nucleic acid docking

Cited by 208 publications

References 32 publications

Chromatin-Bound Oxidized α-Synuclein Causes Strand Breaks in Neuronal Genomes in in vitro Models of Parkinson’s Disease

Chromatin-Bound Oxidized α-Synuclein Causes Strand Breaks in Neuronal Genomes in in vitro Models of Parkinson’s Disease

Transforming growth factor β suppresses peroxisome proliferator-activated receptor γ expression via both SMAD binding and novel TGF-β inhibitory elements

RNA-Puzzles Round III: 3D RNA structure prediction of five riboswitches and one ribozyme

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