scholarly journals Towards the Inhibition of Protein–Protein Interactions (PPIs) in STAT3: Insights into a New Class of Benzothiadiazole Derivatives

Molecules ◽  
2020 ◽  
Vol 25 (15) ◽  
pp. 3509
Author(s):  
Matteo Mori ◽  
Ettore Gilardoni ◽  
Luca Regazzoni ◽  
Alessandro Pedretti ◽  
Diego Colombo ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Malignant Tumors ◽  
Uv Spectroscopy ◽  
Sh2 Domain ◽  
Significant Activity ◽  
Protein Protein Interactions ◽  
New Class ◽  
Mechanism Of Interaction ◽  
The Relationship ◽  
Transcription 3

Signal transducer and activator of transcription 3 (STAT3) is a validated anticancer target due to the relationship between its constitutive activation and malignant tumors. Through a virtual screening approach on the STAT3-SH2 domain, 5,6-dimethyl-1H,3H-2,1,3-benzothiadiazole-2,2-dioxide (1) was identified as a potential STAT3 inhibitor. Some benzothiadiazole derivatives were synthesized by employing a versatile methodology, and they were tested by an AlphaScreen-based assay. Among them, benzosulfamide 1 showed a significant activity with an IC50 = 15.8 ± 0.6 µM as a direct STAT3 inhibitor. Notably, we discovered that compound 1 was also able to interact with cysteine residues located around the SH2 domain. By applying mass spectrometry, liquid chromatography, NMR, and UV spectroscopy, an in-depth investigation was carried out, shedding light on its intriguing and unexpected mechanism of interaction.

scholarly journals Discovery, development and application of drugs targeting BCL-2 pro-survival proteins in cancer

2021 ◽  
Author(s):  
Erinna F. Lee ◽  
W. Douglas Fairlie
Keyword(s):  
Structural Biology ◽  
Protein Interactions ◽  
Basic Science ◽  
Great Success ◽  
Protein Protein Interactions ◽  
New Class ◽  
Success Stories ◽  
History Of ◽  
Approved Drugs ◽  
Close Relatives

The discovery of a new class of small molecule compounds that target the BCL-2 family of anti-apoptotic proteins is one of the great success stories of basic science leading to translational outcomes in the last 30 years. The eponymous BCL-2 protein was identified over 30 years ago due to its association with cancer. However, it was the unveiling of the biochemistry and structural biology behind it and its close relatives’ mechanism(s)-of-action that provided the inspiration for what are now known as ‘BH3-mimetics’, the first clinically approved drugs designed to specifically inhibit protein–protein interactions. Herein, we chart the history of how these drugs were discovered, their evolution and application in cancer treatment.

scholarly journals TC2N: A Novel Vital Oncogene or Tumor Suppressor Gene In Cancers

2021 ◽  
Vol 12 ◽  
Author(s):  
Hanyang Li ◽  
He Fang ◽  
Li Chang ◽  
Shuang Qiu ◽  
Xiaojun Ren ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Tumor Suppressor Gene ◽  
Protein Interactions ◽  
Malignant Tumors ◽  
Suppressor Gene ◽  
C2 Domain ◽  
Protein Protein Interactions ◽  
C2 Domains ◽  
Different Types ◽  
Shock Proteins

Several C2 domain-containing proteins play key roles in tumorigenesis, signal transduction, and mediating protein–protein interactions. Tandem C2 domains nuclear protein (TC2N) is a tandem C2 domain-containing protein that is differentially expressed in several types of cancers and is closely associated with tumorigenesis and tumor progression. Notably, TC2N has been identified as an oncogene in lung and gastric cancer but as a tumor suppressor gene in breast cancer. Recently, a large number of tumor-associated antigens (TAAs), such as heat shock proteins, alpha-fetoprotein, and carcinoembryonic antigen, have been identified in a variety of malignant tumors. Differences in the expression levels of TAAs between cancer cells and normal cells have led to these antigens being investigated as diagnostic and prognostic biomarkers and as novel targets in cancer treatment. In this review, we summarize the clinical characteristics of TC2N-positive cancers and potential mechanisms of action of TC2N in the occurrence and development of specific cancers. This article provides an exploration of TC2N as a potential target for the diagnosis and treatment of different types of cancers.

scholarly journals Multi-Omics Analysis Identifying Key Biomarkers in Ovarian Cancer

2020 ◽  
Vol 27 (1) ◽  
pp. 107327482097667
Author(s):  
Ju-Yueh Li ◽  
Chia-Jung Li ◽  
Li-Te Lin ◽  
Kuan-Hao Tsui
Keyword(s):  
Ovarian Cancer ◽  
Protein Interactions ◽  
Malignant Tumors ◽  
Single Gene ◽  
Protein Protein Interactions ◽  
Normal Tissues ◽  
Human Protein Atlas ◽  
Copy Number Changes ◽  
And Function ◽  
Cancer Tissues

Ovarian cancer is one of the most common malignant tumors. Here, we aimed to study the expression and function of the CREB1 gene in ovarian cancer via the bioinformatic analyses of multiple databases. Previously, the prognosis of ovarian cancer was based on single-factor or single-gene studies. In this study, different bioinformatics tools (such as TCGA, GEPIA, UALCAN, MEXPRESS, and Metascape) have been used to assess the expression and prognostic value of the CREB1 gene. We used the Reactome and cBioPortal databases to identify and analyze CREB1 mutations, copy number changes, expression changes, and protein–protein interactions. By analyzing data on the CREB1 differential expression in ovarian cancer tissues and normal tissues from 12 studies collected from the “Human Protein Atlas” database, we found a significantly higher expression of CREB1 in normal ovarian tissues. Using this database, we collected information on the expression of 25 different CREB-related proteins, including TP53, AKT1, and AKT3. The enrichment of these factors depended on tumor metabolism, invasion, proliferation, and survival. Individualized tumors based on gene therapy related to prognosis have become a new possibility. In summary, we established a new type of prognostic gene profile for ovarian cancer using the tools of bioinformatics.

scholarly journals The Effect of Proline cis-trans Isomerization on the Folding of the C-Terminal SH2 Domain from p85

2019 ◽  
Vol 21 (1) ◽  
pp. 125
Author(s):  
Francesca Troilo ◽  
Francesca Malagrinò ◽  
Lorenzo Visconti ◽  
Angelo Toto ◽  
Stefano Gianni
Keyword(s):  
Protein Interactions ◽  
Specific Interaction ◽  
Sh2 Domain ◽  
Regulatory Subunit ◽  
Wild Type ◽  
Protein Protein Interactions ◽  
Sh2 Domains ◽  
Trans Isomerization ◽  
A Site ◽  
Kinetics Of

SH2 domains are protein domains that modulate protein–protein interactions through a specific interaction with sequences containing phosphorylated tyrosines. In this work, we analyze the folding pathway of the C-terminal SH2 domain of the p85 regulatory subunit of the protein PI3K, which presents a proline residue in a cis configuration in the loop between the βE and βF strands. By employing single and double jump folding and unfolding experiments, we demonstrate the presence of an on-pathway intermediate that transiently accumulates during (un)folding. By comparing the kinetics of folding of the wild-type protein to that of a site-directed variant of C-SH2 in which the proline was replaced with an alanine, we demonstrate that this intermediate is dictated by the peptidyl prolyl cis-trans isomerization. The results are discussed in the light of previous work on the effect of peptidyl prolyl cis-trans isomerization on folding events.

Multivalent peptides displayed on OEGMA-based copolymers for the modulation of protein–protein interactions

2015 ◽  
Vol 6 (45) ◽  
pp. 7862-7870 ◽  
Author(s):  
Yujie Li ◽  
Tao Li ◽  
Jinghui Wang ◽  
Xiaojia Bao ◽  
Yibing Zhao ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Protein Protein Interactions ◽  
Peptide Conjugates ◽  
New Class ◽  
Multiple Copies

We report a new class of copolymer–peptide conjugates which exploits the comb-shaped pOEGMA as a polymeric backbone, into which multiple copies of peptide chains that can modulate intracellular p53–Mdm2 or p53–Mdm4 protein interactions are incorporated.

scholarly journals SKEMPI 2.0: An updated benchmark of changes in protein-protein binding energy, kinetics and thermodynamics upon mutation

2018 ◽  
Author(s):  
Justina Jankauskaitė ◽  
Brian Jiménez-García ◽  
Justas Dapkūnas ◽  
Juan Fernández-Recio ◽  
Iain H. Moal
Keyword(s):  
Binding Energy ◽  
Protein Interactions ◽  
Binding Free Energy ◽  
Molecular Complexes ◽  
Protein Protein Interactions ◽  
Binding Thermodynamics ◽  
Binding Data ◽  
Enthalpy And Entropy Changes ◽  
Enthalpy And Entropy ◽  
The Relationship

AbstractMotivationUnderstanding the relationship between the sequence, structure, binding energy, binding kinetics and binding thermodynamics of protein-protein interactions is crucial to understanding cellular signaling, the assembly and regulation of molecular complexes, the mechanisms through which mutations lead to disease, and protein engineering.ResultsWe present SKEMPI 2.0, a major update to our database of binding free energy changes upon mutation for structurally resolved protein-protein interactions. This version now contains manually curated binding data for 7085 mutations, an increase of 133%, including changes in kinetics for 1844 mutations, enthalpy and entropy changes for 443 mutations, and 440 mutations which abolish detectable binding.AvailabilityThe database is available at https://life.bsc.es/pid/skempi2/

Genetically encoded selective cross-linkers and emerging applications

2020 ◽  
Vol 48 (4) ◽  
pp. 1807-1817
Author(s):  
Haiyan Ren
Keyword(s):  
Protein Interactions ◽  
Unnatural Amino Acids ◽  
Protein Complexes ◽  
Living Cells ◽  
Cross Linking ◽  
Protein Protein Interactions ◽  
New Class ◽  
Selective Reaction ◽  
Biological Studies ◽  
Lower Background

There has been a large amount of interest in the development of genetically encoded cross-linkers that target functional groups naturally present in cells. Recently, a new class of unnatural amino acids that specifically react with target residues were developed and genetically incorporated. The selective reaction shows higher cross-linking efficiency, lower background and predictable cross-linking sites. It has been applied to enhance protein/peptide stability, pinpoint protein–protein interactions, stabilize protein complexes, engineer covalent protein inhibitors, identify phosphatases in living cells, etc. These new covalent linkages provide excellent new tools for protein engineering and biological studies. Their applications in biotherapy will provide considerable opportunities for innovating and improving biomolecular medicines.

Effect of Intestinal Flora Clearance on Liver Proteomics in Mice

2019 ◽  
Vol 16 (3) ◽  
pp. 199-209
Author(s):  
Zhenghu Jia ◽  
Hui Liu ◽  
Mei Song ◽  
Chengmao Yang ◽  
Yapu Zhao ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Concanavalin A ◽  
Intestinal Flora ◽  
Label Free ◽  
Protein Protein Interactions ◽  
Rt Pcr ◽  
Proteome Level ◽  
And Control ◽  
The Relationship ◽  
Free Quantification

Background: Intestinal flora dynamically affects the host&#039;s systemic immune system. Liver is one of the organs that may be affected by intestinal microbiota. </P><P> Materials and Methods: In this study, we aimed to identify proteome level differences between liver tissue from mice cleared intestinal flora and control using tandem mass spectrometry (LC-MS/MS) and label free quantification. Additionally, protein-protein interactions were mapped by STRING, and also, the enrichment of inflammation-related signaling pathways and biological processes was identified using GO and IPA network system. RT-PCR and Western blot were used for validation of the proteomics findings. Results: Our study demonstrated that mice with cleared intestinal flora exhibited decreased sensitivity to Concanavalin A induced acute hepatitis. 324 Proteins in liver were differently expressed after intestinal flora clearance for one week while 210 proteins were differently expressed after intestinal flora clearance for two weeks. Furthermore, five of the identified proteins were validated by western blotting and further investigated by semi-quantitative RT-PCR. Conclusion: Our results showed that intestinal flora clearance in mice could reduce sensitivity to Concanavalin A induced liver injury and influence the expression of proteins in liver, which provides a clue for studying the relationship between gut bacteria and Concanavalin A induced hepatitis.

scholarly journals Coordination complex SH2 domain proteomimetics: an alternative approach to disrupting oncogenic protein–protein interactions

2010 ◽  
Vol 46 (6) ◽  
pp. 892-894 ◽  
Author(s):  
Joel A. Drewry ◽  
Steven Fletcher ◽  
Peibin Yue ◽  
Denys Marushchak ◽  
Wei Zhao ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Sh2 Domain ◽  
Coordination Complex ◽  
Protein Protein Interactions ◽  
Alternative Approach ◽  
Oncogenic Protein

Frataxin, a molecule of mystery: trading stability for function in its iron-binding site

2010 ◽  
Vol 426 (2) ◽  
pp. e1-e3 ◽  
Author(s):  
Darius J. R. Lane ◽  
Des R. Richardson
Keyword(s):  
Binding Site ◽  
Protein Interactions ◽  
Mitochondrial Protein ◽  
Iron Binding ◽  
Protein Protein Interactions ◽  
Iron Sulfur Cluster ◽  
Downstream Effects ◽  
Biochemical Journal ◽  
And Function ◽  
The Relationship

What are the structural implications for iron binding by frataxin, the mitochondrial protein whose decreased expression results in Friedreich's ataxia? Though frataxin has been shown to be essential for proper handling of iron within mitochondria (e.g. for iron–sulfur cluster and haem biosynthesis), its exact molecular function remains unclear. In this issue of the Biochemical Journal, Correia and colleagues investigate the relationship between structure and function at the putative iron-binding site of Yfh1 (yeast frataxin). Using a host of Yfh1 combination point mutants, the authors observe that the presence of a semi-conserved pocket of negative charge within the ‘acidic ridge’ region (thought to be responsible for iron binding) only mildly enhances Yfh1's ability to bind iron, though it does significantly increase the protein's structural flexibility. The general emerging view is that frataxin's keystone role in mitochondrial iron metabolism depends on iron binding. This appears to have downstream effects on protein–protein interactions that are crucial for frataxin function. The current results reveal a somewhat delicate relationship between iron binding and structural plasticity that may help unravel the enigma of frataxin's metabolic roles.

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