Web 3DNA 2.0 for the analysis, visualization, and modeling of 3D nucleic acid structures

Li, Shuxiang; Olson, Wilma K.; Lu, Xiang‐Jun

doi:10.1093/nar/gkz394

Cited by 252 publications

(233 citation statements)

References 37 publications

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“…Our results contribute to RNA structural prediction by providing a complete landscape of notable but previously unidentified non-native secondary structures, that may play a role in regulating frameshifting [23]. Our pseudoknot structural predictions provide alternate starting points and input constraints which can improve the accuracy of existing 3-D physics-based modeling software packages [30,31,32,33,34,35]. Identifying potential initial stems and non-native conformations of the SARS-CoV-2 −1 PRF pseudoknot, while accounting for prevalent mutations to the SARS-CoV-2 virus, will increase the accuracy of RNA structure prediction.…”

Section: Introductionmentioning

confidence: 95%

SARS-CoV-2 ribosomal frameshifting pseudoknot: Improved secondary structure prediction and detection of inter-viral structural similarity

Trinity

Lansing

Jabbari

et al. 2020

Preprint

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to the COVID-19 pandemic; a pandemic of a scale that has not been seen in the modern era. Despite over 29 million reported cases and over 900, 000 deaths worldwide as of September 2020, herd immunity and widespread vaccination efforts by many experts are expected to be insufficient in addressing this crisis for the foreseeable future. Thus, there is an urgent need for treatments that can lessen the effects of SARS-CoV-2 in patients who become seriously affected. Many viruses including HIV, the common cold, SARS-CoV and SARS-CoV-2 use a unique mechanism known as −1 programmed ribosomal frameshifting (−1 PRF) to successfully replicate and infect cells in the human host. SARS-CoV (the coronavirus responsible for SARS) and SARS-CoV-2 possess a unique RNA structure, a three-stemmed pseudoknot, that stimulates −1 PRF. Recent experiments identified that small molecules can be introduced as antiviral agents to bind with the pseudoknot and disrupt its stimulation of −1 PRF. If successfully developed, small molecule therapy that targets −1 PRF in SARS-CoV-2 is an excellent strategy to improve patients’ prognoses. Crucial to developing these successful therapies is modeling the structure of the SARS-CoV-2 −1 PRF pseudoknot. Following a structural alignment approach, we identify similarities in the −1 PRF pseudoknots of the novel coronavirus SARS-CoV-2, the original SARS-CoV, as well as a third coronavirus: MERS-CoV, the coronavirus responsible for Middle East Respiratory Syndrome (MERS). In addition, we provide a better understanding of the SARS-CoV-2 −1 PRF pseudoknot by comprehensively investigating the structural landscape using a hierarchical folding approach. Since understanding the impact of mutations is vital to long-term success of treatments that are based on predicted RNA functional structures, we provide insight on SARS-CoV-2 −1 PRF pseudoknot sequence mutations and their effect on the resulting structure and its function.

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Section: Introductionmentioning

confidence: 95%

SARS-CoV-2 ribosomal frameshifting pseudoknot: Improved secondary structure prediction and detection of inter-viral structural similarity

Trinity

Lansing

Jabbari

et al. 2020

Preprint

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“…The DNA shape parameters were calculated using the web server (http://web.x3dna.org/) (34), with the structures of DRM2-bound DNA molecules as input.…”

Section: Methodsmentioning

confidence: 99%

Substrate deformation regulates DRM2-mediated DNA methylation in plants

Fang¹,

Leichter

Jiang

et al. 2020

Preprint

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1DNA methylation is an important epigenetic mechanism that critically regulates gene 2 expression and genomic stability. In plants, Domains Rearranged Methyltransferase 2 3 (DRM2) preferentially mediates CHH methylation (H=C, T, A), a substrate specificity 4 distinct from that of mammalian DNA methyltransferases. However, the underlying 5 mechanism is unknown. Here, we report structure-function characterizations of DRM2-6 mediated methylation. An arginine finger from the catalytic loop intercalates into DNA 7 minor groove, inducing large DNA deformation that impacts the substrate specificity of 8 DRM2. To accommodate the substrate deformation, the target recognition domain of 9 DRM2 embraces the enlarged DNA major groove via shape complementarity, disruption 10 of which via C397R mutation shifts the substrate specificity of DRM2 toward CHG DNA. 11This study uncovers DNA deformation as a mechanism in regulating the substrate 12 specificity of DRM2, implicative of transposon-specific repression in plants. 13 14 15 16 17 18 19 20 21 22 23 24 25of methylation than the cytosines in the first and second position (16), showing a CHH 1 sub-context specificity. Genomic meta-analysis has also shown that certain trinucleotide 2 contexts, such as CAA and CTA, have a greater methylation frequency than others (e.g. 3 CCC and CCT) (17), supporting a role of sequence context in shaping genomic 4 methylation. Despite these observations, how DNA methyltransferases interplay with 5 substrate sequence to orchestrate distinct DNA methylation patterns at various genomic 6 regions remains unknown. 7 To elucidate the molecular basis of DRM2-mediated CHH methylation, we 8 performed comprehensive structural characterizations of DRM2-substrate complexes 9 and functional validation analysis in vivo. Remarkably, residue R595 from the catalytic 10 core intercalates into the non-target strand, resulting in large DNA deformation, while 11 the target recognition domain (TRD) embraces the deformed DNA major groove via 12 shape complementarity. Biochemical and genome-wide methylation analyses reveal 13 that this DNA deformation permits high methylation efficiency of DRM2 for targets with 14 AT-rich flanking sequences populated in TEs. Substitution of TRD residue C397 with 15 arginine perturbs the shape complementarity between TRD and DNA, shifts the 16 substrate specificity of DRM2 toward the CHG DNA and consequently reshapes the 17 genome-wide DNA methylation patterns. Collectively, this study identified a novel 18 substrate-recognition paradigm for DNA methylation, underpinned by DNA deformation, 19with strong implication in locus-and sequence-specific DNA methylation establishment 20 and maintenance in plants.

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“…The two PaHigA dimers bind to the B-form DNA duplex symmetrically, where each dimer bound on the opposite sides (Figures 2A,B). The average width of the major groove and minor groove of the promoter DNA is 18.4 and 12.7 Å, respectively, whereas they are 17.2 and 11.7 Å in the ideal B-form DNA, respectively, which are calculated by the w3DNA web server (Supplementary Figure S3) (Li et al, 2019). The two identical palindromic sequences are essentially encircled by the two PaHigA dimers simultaneously.…”

Section: Two Pahiga Dimers Bind To Pahigba Promoter Dna Symmetricallymentioning

confidence: 99%

Structural Insights Into the Transcriptional Regulation of HigBA Toxin–Antitoxin System by Antitoxin HigA in Pseudomonas aeruginosa

et al. 2020

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HigB-HigA is a bacterial toxin-antitoxin (TA) system in which the antitoxin HigA can mask the endoribonuclease activity of toxin HigB and repress the transcription of the TA operon by binding to its own promoter region. The opportunistic pathogen Pseudomonas aeruginosa HigBA (PaHigBA) is closely associated with the pathogenicity by reducing the production of multiple virulence factors and biofilm formation. However, the molecular mechanism underlying HigBA TA operon transcription by PaHigA remains elusive. Here, we report the crystal structure of PaHigA binding to the promoter region of higBA operon containing two identical palindromic sequences at 3.14 Å resolution. The promoter DNA is bound by two cooperative dimers to essentially encircle the intact palindrome region. The helix-turn-helix (HTH) motifs from the two dimers insert into the major grooves of the DNA at the opposite sides. The DNA adopts a canonical B-DNA conformation and all the hydrogen bonds between protein and DNA are mediated by the DNA phosphate backbone. A higher resolution structure of PaHigA-DNA complex at 2.50 Å further revealed three water molecules bridged the DNA-binding interface and mediated the interactions between the bases of palindromic sequences and PaHigA (Thr40, Asp43, and Arg49). Structure-based mutagenesis confirmed these residues are essential for the specific DNA-binding ability of PaHigA. Our structure-function studies therefore elucidated the cooperative dimer-dimer transcription repression mechanism, and may help to understand the regulation of multiple virulence factors by PaHigA in P. aeruginosa.

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Web 3DNA 2.0 for the analysis, visualization, and modeling of 3D nucleic acid structures

Cited by 252 publications

References 37 publications

SARS-CoV-2 ribosomal frameshifting pseudoknot: Improved secondary structure prediction and detection of inter-viral structural similarity

SARS-CoV-2 ribosomal frameshifting pseudoknot: Improved secondary structure prediction and detection of inter-viral structural similarity

Substrate deformation regulates DRM2-mediated DNA methylation in plants

Structural Insights Into the Transcriptional Regulation of HigBA Toxin–Antitoxin System by Antitoxin HigA in Pseudomonas aeruginosa

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