Residue interaction network analysis of Dronpa and a DNA clamp

Hu, Guang; Yan, Wenying; Zhou, Jianhong; Shen, Bairong

doi:10.1016/j.jtbi.2014.01.023

Cited by 62 publications

(43 citation statements)

References 52 publications

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“…One of the features of a RCA is that it can identify residues that are central to the structural integrity and play key roles in long‐range interactions. These residues have been shown to be important for protein function, fold or allosteric communication . We have focused our attention on the residues of Ets‐1 and considered as central those with a z score ≥ 2 (Table ).…”

Section: Resultsmentioning

confidence: 99%

“…These residues have been shown to be important for protein function, fold or allosteric communication. 32,33,[43][44][45] We have focused our attention on the residues of Ets-1 and considered as central those with a z score ≥ 2 (Table 1). Since the calculations have been performed on the structures of the complexes, we can therefore consider the residues on ETS emerging from these calculations to be important for the structural integrity of either the individual domain or the complex as a whole.…”

Section: Evaluation Of Identified Hot Spots At the Interaction Intementioning

confidence: 99%

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Computational characterization of the binding mode between oncoprotein Ets‐1 and DNA‐repair enzymes

et al. 2018

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The Ets‐1 oncoprotein is a transcription factor that promotes target gene expression in specific biological processes. Typically, Ets‐1 activity is low in healthy cells, but elevated levels of expression have been found in cancerous cells, specifically related to tumor progression. Like the vast majority of the cellular effectors, Ets‐1 does not act alone but in association with partners. Given the important role that is attributed to Ets‐1 in major human diseases, it is crucial to identify its partners and characterize their interactions. In this context, two DNA‐repair enzymes, PARP‐1 and DNA‐PK, have been identified recently as interaction partners of Ets‐1. We here identify their binding mode by means of protein docking. The results identify the interacting surface between Ets‐1 and the two DNA‐repair enzymes centered on the α‐helix H1 of the ETS domain, leaving α‐helix H3 available to bind DNA. The models highlight a hydrophobic patch on Ets‐1 at the center of the interaction interface that includes three tryptophans (Trp338, Trp356, and Trp361). We rationalize the binding mode using a series of computational analyses, including alanine scanning, molecular dynamics simulation, and residue centrality analysis. Our study constitutes a first but important step in the characterization, at the molecular level, of the interaction between an oncoprotein and DNA‐repair enzymes.

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Section: Resultsmentioning

confidence: 99%

Section: Evaluation Of Identified Hot Spots At the Interaction Intementioning

confidence: 99%

Computational characterization of the binding mode between oncoprotein Ets‐1 and DNA‐repair enzymes

et al. 2018

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“…From the point of view of applications, it is important to note that network-based studies of proteins can help in identifying drug target candidates (Csermely et al 2013). Different measures of centrality have been investigated in PCNs in order to understand the role played by different residues in the architectural organization of a protein (Hu et al 2014). Several studies have also explored the occurrence of intermediate-scale (or mesoscopic) features of PCNs such as modularity by exploring sub-domain architecture using community detection algorithms (Hleap et al 2013).…”

Section: Introductionmentioning

confidence: 99%

Analysis of core–periphery organization in protein contact networks reveals groups of structurally and functionally critical residues

Emerson

Sinha

2015

J Biosci

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The representation of proteins as networks of interacting amino acids, referred to as protein contact networks (PCN), and their subsequent analyses using graph theoretic tools, can provide novel insights into the key functional roles of specific groups of residues. We have characterized the networks corresponding to the native states of 66 proteins (belonging to different families) in terms of their core-periphery organization. The resulting hierarchical classification of the amino acid constituents of a protein arranges the residues into successive layers - having higher core order - with increasing connection density, ranging from a sparsely linked periphery to a densely intra-connected core (distinct from the earlier concept of protein core defined in terms of the three-dimensional geometry of the native state, which has least solvent accessibility). Our results show that residues in the inner cores are more conserved than those at the periphery. Underlining the functional importance of the network core, we see that the receptor sites for known ligand molecules of most proteins occur in the innermost core. Furthermore, the association of residues with structural pockets and cavities in binding or active sites increases with the core order. From mutation sensitivity analysis, we show that the probability of deleterious or intolerant mutations also increases with the core order. We also show that stabilization centre residues are in the innermost cores, suggesting that the network core is critically important in maintaining the structural stability of the protein. A publicly available Web resource for performing core-periphery analysis of any protein whose native state is known has been made available by us at http://www.imsc.res.in/ ~sitabhra/proteinKcore/index.html.

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“…Residue‐residue interaction within a protein network is integral in maintaining its 3D structural integrity, which is crucial for its biological activity that can involve interactions with other biomolecules. Therefore, a disruption or disorganization in residue interaction and network topology could possibly result in protein dysfunctionality or inactivation . In this study, possible disruptions in the p53 network topology that is induced by mutations (R273C and R175H) were evaluated to further understand the molecular basis of p53 loss of DNA binding; hence, respective network topologies were analyzed to highlight the protein‐DNA binding interface.…”

Section: Resultsmentioning

confidence: 99%

Dynamic perspectives into the mechanisms of mutation‐induced p53‐DNA binding loss and inactivation using active perturbation theory: Structural and molecular insights toward the design of potent reactivators in cancer therapy

Olotu

2018

J of Cellular Biochemistry

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The DNA-binding ability of p53 represents the crux of its tumor suppressive activities, which involves transcriptional activation of target genes responsible for apoptosis and cell-cycle arrest. Mutational occurrences within or in close proximity to the DNA-binding surface of p53 have accounted for the loss of direct DNA-binding ability and inactivation implicated in many cases of cancer. Moreover, the design of therapeutic compounds that can restore DNA-binding ability in p53 mutants has been identified as a way forward in curtailing their oncogenic activities. However, there is still the need for more insights into evaluate the perturbations that occur at the DNA-binding interface of mp53 relative to DNA-binding loss, inactivation, and design of potent reactivators, hence the purpose of this study. Therefore, we evaluated p53-structural (R175H) and contact (R273C) mutational effects using tunnel perturbation analysis and other computational tools. We identified significant perturbations in the active tunnels of p53, which resulted in altered geometry and loss, unlike in the wild-type p53. This corroborated with structural, DNA-binding, and interaction network analysis, which showed that loss of flexibility, repulsion of DNA-interactive residues, and instability occurred at the binding interface of both mutants. Also, these mutations altered bonding interactions and network topology at the DNA-binding interface, resulting in the reduction of p53-DNA binding proximity and affinity. Therefore, these findings would aid the structure-based design of novel chemical entities capable of restoring p53-DNA binding and activation.

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Residue interaction network analysis of Dronpa and a DNA clamp

Cited by 62 publications

References 52 publications

Computational characterization of the binding mode between oncoprotein Ets‐1 and DNA‐repair enzymes

Computational characterization of the binding mode between oncoprotein Ets‐1 and DNA‐repair enzymes

Analysis of core–periphery organization in protein contact networks reveals groups of structurally and functionally critical residues

Dynamic perspectives into the mechanisms of mutation‐induced p53‐DNA binding loss and inactivation using active perturbation theory: Structural and molecular insights toward the design of potent reactivators in cancer therapy

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