scholarly journals Structures of Human Transglutaminase 2: Finding Clues for Interference in Cross-linking Mediated Activity

2020 ◽  
Vol 21 (6) ◽  
pp. 2225
Author(s):  
Gi Eob Kim ◽  
Hyun Ho Park
Keyword(s):  
Neurodegenerative Disorders ◽  
Active Site ◽  
Drug Target ◽  
Structural Information ◽  
Transglutaminase 2 ◽  
Cross Linking ◽  
Targeted Drugs ◽  
Clinical Use ◽  
Structural Studies ◽  
Cellular Processes

Human transglutaminase 2 (TGase2) has various functions, including roles in various cellular processes such as apoptosis, development, differentiation, wound healing, and angiogenesis, and is linked to many diseases such as cancer. Although TGase2 has been considered an optimized drug target for the treatment of cancer, fibrosis, and neurodegenerative disorders, it has been difficult to generate TGase2-targeted drugs for clinical use because of the relatively flat and broad active site on TGase2. To design more specific and powerful inhibitors, detailed structural information about TGase2 complexed with various effector and inhibitor molecules is required. In this review, we summarized the current structural studies on TGase2, which will aid in designing drugs that can overcome the aforementioned limitations.

scholarly journals The structure of the metallo-β-lactamase VIM-2 in complex with a triazolylthioacetamide inhibitor

2016 ◽  
Vol 72 (11) ◽  
pp. 813-819 ◽  
Author(s):  
Tony Christopeit ◽  
Ke-Wu Yang ◽  
Shao-Kang Yang ◽  
Hanna-Kirsti S. Leiros
Keyword(s):  
Public Health ◽  
Crystal Structure ◽  
Active Site ◽  
Drug Target ◽  
Zinc Ions ◽  
Clinical Use ◽  
Global Public Health ◽  
Promising Strategy ◽  
Conserved Residue ◽  
Substrate Spectrum

The increasing number of pathogens expressing metallo-β-lactamases (MBLs), and in this way achieving resistance to β-lactam antibiotics, is a significant threat to global public health. A promising strategy to treat such resistant pathogens is the co-administration of MBL inhibitors together with β-lactam antibiotics. However, an MBL inhibitor suitable for clinical use has not yet been identified. Verona integron-encoded metallo-β-lactamase 2 (VIM-2) is a widespread MBL with a broad substrate spectrum and hence is an interesting drug target for the treatment of β-lactam-resistant infections. In this study, three triazolylthioacetamides were tested as inhibitors of VIM-2. One of the tested compounds showed clear inhibition of VIM-2, with an IC50of 20 µM. The crystal structure of the inhibitor in complex with VIM-2 was obtained by DMSO-free co-crystallization and was solved at a resolution of 1.50 Å. To our knowledge, this is the first structure of a triazolylthioacetamide inhibitor in complex with an MBL. Analysis of the structure shows that the inhibitor binds to the two zinc ions in the active site of VIM-2 and revealed detailed information on the interactions involved. Furthermore, the crystal structure showed that binding of the inhibitor induced a conformational change of the conserved residue Trp87.

scholarly journals Modulation of Monomer Conformation of the BglG Transcriptional Antiterminator from Escherichia coli

2004 ◽  
Vol 186 (20) ◽  
pp. 6775-6781 ◽  
Author(s):  
Liat Fux ◽  
Anat Nussbaum-Shochat ◽  
Livnat Lopian ◽  
Orna Amster-Choder
Keyword(s):  
Escherichia Coli ◽  
Active Site ◽  
Rna Binding ◽  
Cross Linking ◽  
Structural Studies ◽  
Phosphorylated Proteins ◽  
Close Proximity ◽  
Compact Conformation

ABSTRACT The BglG protein positively regulates expression of the bgl operon in Escherichia coli by binding as a dimer to the bgl transcript and preventing premature termination of transcription in the presence of β-glucosides. BglG activity is negatively controlled by BglF, the β-glucoside phosphotransferase, which reversibly phosphorylates BglG according to β-glucoside availability, thus modulating its dimeric state. BglG consists of an RNA-binding domain and two homologous domains, PRD1 and PRD2. Based on structural studies of a BglG homologue, the two PRDs fold similarly, and the interactions within the dimer are PRD1-PRD1 and PRD2-PRD2. We have recently shown that the affinity between PRD1 and PRD2 of BglG is high, and a fraction of the BglG monomers folds in the cell into a compact conformation, in which PRD1 and PRD2 are in close proximity. We show here that both BglG forms, the compact and noncompact, bind to the active site-containing domain of BglF, IIBbgl, in vitro. The interaction of BglG with IIBbgl or BglF is mediated by PRD2. Both BglG forms are detected as phosphorylated proteins after in vitro phosphorylation with IIBbgl and are dephosphorylated by BglF in vitro in the presence of β-glucosides. Nevertheless, genetic evidence indicates that the interaction of IIBbgl and BglF with the compact form is seemingly less favorable. Using in vivo cross-linking, we show that BglF enhances folding of BglG into a compact conformation, whereas the addition of β-glucosides reduces the amount of this form. Based on these results we suggest a model for the modulation of BglG conformation and activity by BglF.

scholarly journals A Structural Approach into Drug Discovery Based on Autophagy

Life ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 526
Author(s):  
Sung-Min Kang ◽  
Do-Hee Kim
Keyword(s):  
High Throughput Screening ◽  
Drug Target ◽  
Metabolic Diseases ◽  
Structural Information ◽  
Screening Methods ◽  
Structural Studies ◽  
Intracellular Degradation ◽  
Structure Activity ◽  
Related Proteins ◽  
Novel Drug

Autophagy is a lysosome-dependent intracellular degradation machinery that plays an essential role in the regulation of cellular homeostasis. As many studies have revealed that autophagy is related to cancer, neurodegenerative diseases, metabolic diseases, and so on, and it is considered as a promising drug target. Recent advances in structural determination and computational technologies provide important structural information on essential autophagy-related proteins. Combined with high-throughput screening methods, structure-activity relationship studies have led to the discovery of molecules that modulate autophagy. In this review, we summarize the recent structural studies on autophagy-related proteins and the discovery of modulators, indicating that targeting autophagy can be utilized as an effective strategy for novel drug development.

Structural studies of small amorphous volumes by electron diffraction

1990 ◽  
Vol 48 (4) ◽  
pp. 122-123
Author(s):  
Pierre Moine
Keyword(s):  
Electron Diffraction ◽  
Born Approximation ◽  
Structural Information ◽  
Fundamental Relation ◽  
X Rays ◽  
Structural Studies ◽  
Diffraction Experiment ◽  
Transmission Electron ◽  
Amorphous Structures ◽  
Diffraction Patterns

Qualitatively, amorphous structures can be easily revealed and differentiated from crystalline phases by their Transmission Electron Microscopy (TEM) images and their diffraction patterns (fig.1 and 2) but, for quantitative structural information, electron diffraction pattern intensity analyses are necessary. The parameters describing the structure of an amorphous specimen have been introduced in the context of scattering experiments which have been, so far, the most used techniques to obtain structural information in the form of statistical averages. When only small amorphous volumes (< 1/μm in size or thickness) are available, the much higher scattering of electrons (compared to neutrons or x rays) makes, despite its drawbacks, electron diffraction extremely valuable and often the only feasible technique.In a diffraction experiment, the intensity IN (Q) of a radiation, elastically scattered by N atoms of a sample, is measured and related to the atomic structure, using the fundamental relation (Born approximation) : IN(Q) = |FT[U(r)]|.

Use of Molecular Dynamics Simulations in Structure-Based Drug Discovery

2019 ◽  
Vol 25 (31) ◽  
pp. 3339-3349 ◽  
Author(s):  
Indrani Bera ◽  
Pavan V. Payghan
Keyword(s):  
Molecular Dynamics ◽  
Drug Discovery ◽  
Molecular Dynamics Simulations ◽  
Drug Target ◽  
Structural Information ◽  
Drug Binding ◽  
Structure Based Drug Design ◽  
Drug Designing ◽  
Target Binding ◽  
Dynamics Simulations

Background: Traditional drug discovery is a lengthy process which involves a huge amount of resources. Modern-day drug discovers various multidisciplinary approaches amongst which, computational ligand and structure-based drug designing methods contribute significantly. Structure-based drug designing techniques require the knowledge of structural information of drug target and drug-target complexes. Proper understanding of drug-target binding requires the flexibility of both ligand and receptor to be incorporated. Molecular docking refers to the static picture of the drug-target complex(es). Molecular dynamics, on the other hand, introduces flexibility to understand the drug binding process. Objective: The aim of the present study is to provide a systematic review on the usage of molecular dynamics simulations to aid the process of structure-based drug design. Method: This review discussed findings from various research articles and review papers on the use of molecular dynamics in drug discovery. All efforts highlight the practical grounds for which molecular dynamics simulations are used in drug designing program. In summary, various aspects of the use of molecular dynamics simulations that underline the basis of studying drug-target complexes were thoroughly explained. Results: This review is the result of reviewing more than a hundred papers. It summarizes various problems that use molecular dynamics simulations. Conclusion: The findings of this review highlight how molecular dynamics simulations have been successfully implemented to study the structure-function details of specific drug-target complexes. It also identifies the key areas such as stability of drug-target complexes, ligand binding kinetics and identification of allosteric sites which have been elucidated using molecular dynamics simulations.

scholarly journals Nuclear condensates of p300 formed though the structured catalytic core can act as a storage pool of p300 with reduced HAT activity

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yi Zhang ◽  
Kyle Brown ◽  
Yucong Yu ◽  
Ziad Ibrahim ◽  
Mohamad Zandian ◽  
...  
Keyword(s):  
Phase Separation ◽  
Cell Nucleus ◽  
Active Site ◽  
Histone Acetyltransferase ◽  
Histone H3 ◽  
Catalytic Core ◽  
Cellular Processes ◽  
Storage Pool ◽  
Core Components ◽  
Acetyltransferase P300

AbstractThe transcriptional co-activator and acetyltransferase p300 is required for fundamental cellular processes, including differentiation and growth. Here, we report that p300 forms phase separated condensates in the cell nucleus. The phase separation ability of p300 is regulated by autoacetylation and relies on its catalytic core components, including the histone acetyltransferase (HAT) domain, the autoinhibition loop, and bromodomain. p300 condensates sequester chromatin components, such as histone H3 tail and DNA, and are amplified through binding of p300 to the nucleosome. The catalytic HAT activity of p300 is decreased due to occlusion of the active site in the phase separated droplets, a large portion of which co-localizes with chromatin regions enriched in H3K27me3. Our findings suggest a model in which p300 condensates can act as a storage pool of the protein with reduced HAT activity, allowing p300 to be compartmentalized and concentrated at poised or repressed chromatin regions.

scholarly journals A Novel Method to Predict Drug-Target Interactions Based on Large-Scale Graph Representation Learning

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2111
Author(s):  
Bo-Wei Zhao ◽  
Zhu-Hong You ◽  
Lun Hu ◽  
Zhen-Hao Guo ◽  
Lei Wang ◽  
...  
Keyword(s):  
Drug Target ◽  
Large Scale ◽  
Computational Models ◽  
Structural Information ◽  
Characteristic Curve ◽  
Representation Learning ◽  
Graph Representation ◽  
Convolutional Network ◽  
Novel Method

Identification of drug-target interactions (DTIs) is a significant step in the drug discovery or repositioning process. Compared with the time-consuming and labor-intensive in vivo experimental methods, the computational models can provide high-quality DTI candidates in an instant. In this study, we propose a novel method called LGDTI to predict DTIs based on large-scale graph representation learning. LGDTI can capture the local and global structural information of the graph. Specifically, the first-order neighbor information of nodes can be aggregated by the graph convolutional network (GCN); on the other hand, the high-order neighbor information of nodes can be learned by the graph embedding method called DeepWalk. Finally, the two kinds of feature are fed into the random forest classifier to train and predict potential DTIs. The results show that our method obtained area under the receiver operating characteristic curve (AUROC) of 0.9455 and area under the precision-recall curve (AUPR) of 0.9491 under 5-fold cross-validation. Moreover, we compare the presented method with some existing state-of-the-art methods. These results imply that LGDTI can efficiently and robustly capture undiscovered DTIs. Moreover, the proposed model is expected to bring new inspiration and provide novel perspectives to relevant researchers.

scholarly journals The Active Site of a Prototypical “Rigid” Drug Target is Marked by Extensive Conformational Dynamics

2020 ◽  
Vol 59 (51) ◽  
pp. 22916-22921
Author(s):  
Himanshu Singh ◽  
Chandan K. Das ◽  
Suresh K. Vasa ◽  
Kristof Grohe ◽  
Lars V. Schäfer ◽  
...  
Keyword(s):  
Active Site ◽  
Drug Target ◽  
Conformational Dynamics

Screening ,development of Transglutaminase-2 Inhibitors and its derivative as anti-lung cancer agent by insilico and invitro approach

2021 ◽  
Vol 17 ◽  
Author(s):  
Prachi P. Parvatikar ◽  
Sumangala Patil ◽  
Joy Hoskeri ◽  
Sandeep Swargam ◽  
Raghvendra Kulkarni ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Transglutaminase 2 ◽  
Docking Studies ◽  
Target Protein ◽  
Cellular Processes ◽  
Cytotoxicity Studies ◽  
Pharmacokinetic Properties ◽  
Cancer Agent ◽  
Inhibition Property ◽  
Cancer Inhibition

Aim: Screening and development of TG2 inhibitors as anti lung cancer agent. Background: Transglutaminase 2 (TG2) is multifunctional and ubiquitously expressed protein from transglutaminase family. It takes part in various cellular processes and plays an important role in the pathogenesis of autoimmune, neurodegerative and also cancer. Background: Transglutaminase 2 (TG2) is multifunctional and ubiquitously expressed protein from transglutaminase family. It takes part in various cellular processes and plays an important role in the pathogenesis of autoimmune, neurodegerative and also cancer. Objective : The of proposed study is to focused on screening of potent inhibitors of TG2 by in-silico method and synthesis its derivative as well as analysis of its activity by invitro approach. Material and Methods: Molecular docking studies have been carried on the different classes of TG2 inhibitors against the target protein. Nearly thirty TG2 inhibitors were selected from literature and docking was performed against transglutaminase 2. The computational ADME property screening was also carried out to check their pharmacokinetic properties. The compounds which exhibited positive ADME properties with good interaction with possessing least binding energy were further validated for their anti-lung cancer inhibition property against A549 cell lines by cytotoxicity studies. Results: The results of present study indicate that the docked complex formed by cystamine showed better binding affinity towards target protein so, this derivative of cystamine is formed using 2,5 dihydrobenzoic acid. Invitro results revealed that both molecule proved good cytotoxic agent against A549 lung cancer (875.10, 553.22 µg/ml) respectively. Further its activity should be validated on TG2 expressing lung cancer. Conclusion : Cystamine and its derivative can be act as potential therapeutic target for lung cancer but further its activity should be validated on TG2 expressing lung cancer.

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