LARMD: integration of bioinformatic resources to profile ligand-driven protein dynamics with a case on the activation of estrogen receptor

2019 ◽  
Vol 21 (6) ◽  
pp. 2206-2218 ◽  
Author(s):  
Jing-Fang Yang ◽  
Fan Wang ◽  
Yu-Zong Chen ◽  
Ge-Fei Hao ◽  
Guang-Fu Yang
Keyword(s):  
Estrogen Receptor ◽  
Protein Dynamics ◽  
Protein Function ◽  
Inflammatory Diseases ◽  
Great Difficulty ◽  
Vital Role ◽  
Site Directed Mutagenesis ◽  
Bioinformatic Tools ◽  
Wide Range ◽  
User Friendly

Abstract Protein dynamics is central to all biological processes, including signal transduction, cellular regulation and biological catalysis. Among them, in-depth exploration of ligand-driven protein dynamics contributes to an optimal understanding of protein function, which is particularly relevant to drug discovery. Hence, a wide range of computational tools have been designed to investigate the important dynamic information in proteins. However, performing and analyzing protein dynamics is still challenging due to the complicated operation steps, giving rise to great difficulty, especially for nonexperts. Moreover, there is a lack of web protocol to provide online facility to investigate and visualize ligand-driven protein dynamics. To this end, in this study, we integrated several bioinformatic tools to develop a protocol, named Ligand and Receptor Molecular Dynamics (LARMD, http://chemyang.ccnu.edu.cn/ccb/server/LARMD/ and http://agroda.gzu.edu.cn:9999/ccb/server/LARMD/), for profiling ligand-driven protein dynamics. To be specific, estrogen receptor (ER) was used as a case to reveal ERβ-selective mechanism, which plays a vital role in the treatment of inflammatory diseases and many types of cancers in clinical practice. Two different residues (Ile373/Met421 and Met336/Leu384) in the pocket of ERβ/ERα were the significant determinants for selectivity, especially Met336 of ERβ. The helix H8, helix H11 and H7-H8 loop influenced the migration of selective agonist (WAY-244). These computational results were consistent with the experimental results. Therefore, LARMD provides a user-friendly online protocol to study the dynamic property of protein and to design new ligand or site-directed mutagenesis.

scholarly journals Protein dynamics enables phosphorylation of buried residues in Cdk2/Cyclin A-bound p27

2020 ◽  
Author(s):  
João Henriques ◽  
Kresten Lindorff-Larsen
Keyword(s):  
Protein Phosphorylation ◽  
Protein Dynamics ◽  
Single Molecule ◽  
Protein Function ◽  
Cell Cycle Progression ◽  
Conformational Dynamics ◽  
Protein Structures ◽  
Cyclin A ◽  
General Role ◽  
Wide Range

AbstractProteins carry out a wide range of functions that are tightly regulated in space and time. Protein phosphorylation is the most common post-translation modification of proteins and plays key roles in the regulation of many biological processes. The finding that many phosphorylated residues are not solvent exposed in the unphosphorylated state opens several questions for understanding the mechanism that underlies phosphorylation and how phosphorylation may affect protein structures. First, since kinases need access to the phosphorylated residue, how do such buried residues become modified? Second, once phosphorylated, what are the structural effects of phosphorylation of buried residues and do they lead to changed conformational dynamics. We have used the ternary complex between p27, Cdk2 and Cyclin A to study these questions using enhanced sampling molecular dynamics simulations. In line with previous NMR and single-molecule fluorescence experiments we observe transient exposure of Tyr88 in p27, even in its unphosphorylated state. Once Tyr88 is phosphorylated, we observe a coupling to a second site, thus making Tyr74 more easily exposed, and thereby the target for a second phosphorylation step. Our observations provide atomic details on how protein dynamics plays a role in modulating multi-site phosphorylation in p27, thus supplementing previous experimental observations. More generally, we discuss how the observed phenomenon of transient exposure of buried residues may play a more general role in regulating protein function.Significance StatementProtein phosphorylation is a common post-translation modification and is carried out by kinases. While many phosphorylation sites are located in disordered regions of proteins or in loops, a surprisingly large number of modification sites are buried inside folded domains. This observation led us to ask the question of how kinases gain access to such buried residues. We used the complex between p27, a regulator of cell cycle progression, and Cyclin-dependent kinase 2/Cyclin A to study this problem. We hypothesized that transient exposure of buried tyrosines in p27 to the solvent would make them accessible to kinases, explaining how buried residues get modified. We provide an atomic-level description of these dynamic processes revealing how protein dynamics plays a role in regulation.

scholarly journals Nanopores: a versatile tool to study protein dynamics

2020 ◽  
Author(s):  
Sonja Schmid ◽  
Cees Dekker
Keyword(s):  
Protein Dynamics ◽  
Single Molecule ◽  
Conformational Changes ◽  
Protein Function ◽  
Label Free ◽  
Cellular Functions ◽  
Ensemble Averaging ◽  
Time Resolved ◽  
Wide Range ◽  
Versatile Tool

Abstract Proteins are the active workhorses in our body. These biomolecules perform all vital cellular functions from DNA replication and general biosynthesis to metabolic signaling and environmental sensing. While static 3D structures are now readily available, observing the functional cycle of proteins – involving conformational changes and interactions – remains very challenging, e.g., due to ensemble averaging. However, time-resolved information is crucial to gain a mechanistic understanding of protein function. Single-molecule techniques such as FRET and force spectroscopies provide answers but can be limited by the required labelling, a narrow time bandwidth, and more. Here, we describe electrical nanopore detection as a tool for probing protein dynamics. With a time bandwidth ranging from microseconds to hours, nanopore experiments cover an exceptionally wide range of timescales that is very relevant for protein function. First, we discuss the working principle of label-free nanopore experiments, various pore designs, instrumentation, and the characteristics of nanopore signals. In the second part, we review a few nanopore experiments that solved research questions in protein science, and we compare nanopores to other single-molecule techniques. We hope to make electrical nanopore sensing more accessible to the biochemical community, and to inspire new creative solutions to resolve a variety of protein dynamics – one molecule at a time.

Heparin and proteoglycans as anti-inflammatory drugs

1996 ◽  
Vol 16 (01) ◽  
pp. 56-59
Author(s):  
D. J. Tyrrell ◽  
C. P. Page
Keyword(s):  
Inflammatory Diseases ◽  
Therapeutic Applications ◽  
Wide Range ◽  
Inflammatory Drugs ◽  
Anti Inflammatory

SummaryEvidence continues to accumulate that the pleiotropic nature of heparin (beyond its anticoagulant potency) includes anti-inflammatory activities at a number of levels. It is clear that drugs exploiting these anti-inflammatory activities of heparin may offer exciting new therapeutic applications to the treatment of a wide range of inflammatory diseases.

Comparative Study on Mitogen Activated Protein Kinase of Plasmodium Species by Using In silico Method

2012 ◽  
Vol 9 (1) ◽  
pp. 1
Author(s):  
Mohd Fakharul Zaman Raja Yahya ◽  
Hasidah Mohd Sidek
Keyword(s):  
Amino Acid ◽  
In Silico ◽  
Nuclear Export ◽  
Nuclear Export Signal ◽  
Plasmodium Species ◽  
Mitogen Activated Protein Kinase ◽  
Multiple Sequence ◽  
Bioinformatic Tools ◽  
Wide Range ◽  
Human Plasmodium

Malaria parasites, Plasmodium can infect a wide range ofhosts including humans and rodents. There are two copies ofmitogen activated protein kinases (MAPKs) in Plasmodium, namely MAPK1 and MAPK2. The MAPKs have been studied extensively in the human Plasmodium, P. falciparum. However, the MAPKs from other Plasmodium species have not been characterized and it is therefore the premise ofpresented study to characterize the MAPKs from other Plasmodium species-P. vivax, P. knowlesi, P. berghei, P. chabaudi and P.yoelli using a series ofpublicly available bioinformatic tools. In silico data indicates that all Plasmodium MAPKs are nuclear-localizedandcontain both a nuclear localization signal (NLS) anda Leucine-rich nuclear export signal (NES). The activation motifs ofTDYand TSH werefound to befully conserved in Plasmodium MAPK1 and MAPK2, respectively. The detailed manual inspection ofa multiple sequence alignment (MSA) construct revealed a total of 17 amino acid stack patterns comprising ofdifferent amino acids present in MAPK1 and MAPK2 respectively, with respect to rodent and human Plasmodia. 1t is proposed that these amino acid stack patterns may be useful in explaining the disparity between rodent and human Plasmodium MAPKs.

OCCURRENCE OF THE RISKS FOR DEVELOPMENT OF RESPIRATORY DISEASES IN CHILDREN EXPOSED TO THE CHEMICAL FACTORS OF THE EXPOSURE OF ALUMINA REFINERY- ASSOCIATED BUSINESS ACTIVITY

2019 ◽  
pp. 42-47 ◽  
Author(s):  
M.A. Zemlianova ◽  
I.V. Tikhonova
Keyword(s):  
Respiratory Tract ◽  
Respiratory Diseases ◽  
Inflammatory Diseases ◽  
Allergic Inflammation ◽  
Respiratory Morbidity ◽  
Upper Respiratory Tract ◽  
Negative Effects ◽  
Wide Range ◽  
Chemical Factors ◽  
Chronic Lymphoproliferative Diseases

Alumina refineries are among the leading sources of atmospheric air pollution with a wide range of pollutants hazardous to human respiratory organs. It is relevant to study and evaluate the occurrence of the risks for development of respiratory diseases in children living in the area affected by the emission components of an alumina refinery. We assessed air quality of the area under observation and comparison according to monitoring observations, risk of non-carcinogenic effects from the respiratory organs. The content of chemicals in the blood and urine adequate to risk factors was quantified. The structure of individual groups of respiratory diseases was analyzed. The causal relationships of violations of laboratory parameters with an increased content of chemicals in biological media were evaluated. It was found that an aerogenic exposure of chemical pollutants is formed on the territory with the production of metallurgical alumina. It determines the risk for development of respiratory diseases, exceeding an acceptable level up to 49.9 times. In the exposed children, the content of manganese, chromium, nickel, copper, xylenes, formaldehyde and aluminum, fluoride ion in the urine was increased to 4.2 times in relation to the indices in the comparison group. A high level of additional respiratory morbidity(1.8 times) was revealed. Chronic lymphoproliferative diseases of the nasopharynx and inflammatory diseases of the upper respiratory tract (up to 6.6 times more often), inflammatory diseases with a predominance of the mechanism of allergic inflammation ( up to 2.1 times more often)are more often detected in the framework of the respiratory diseases. Negative effects on the part of the respiratory system in the form of activation of antioxidant processes, the development of an inflammatory reaction, local, general and specific sensitization of the respiratory tract were established. It confirms the occurrence of the risks for the development of respiratory diseases in children in the exposure area of the chemical factors of alumina refinery-associated economic activity.

Logical Structure for User Friendly dynamic Web Page Visualization for Small Screen Terminals Promoting E-Business

2020 ◽  
Vol 14 ◽  
Author(s):  
Shefali Singhal ◽  
Poonam Tanwar
Keyword(s):  
Logical Structure ◽  
Vital Role ◽  
Web Pages ◽  
Main Concern ◽  
Web Page ◽  
Large Screen ◽  
Tree Data ◽  
Tree Data Structure ◽  
User Friendly ◽  
Small Screen

Abstract:: Now-a-days when everything is going digitalized, internet and web plays a vital role in everyone’s life. When one has to ask something or has any online task to perform, one has to use internet to access relevant web-pages throughout. These web-pages are mainly designed for large screen terminals. But due to mobility, handy and economic reasons most of the persons are using small screen terminals (SST) like mobile phone, palmtop, pagers, tablet computers and many more. Reading a web page which is actually designed for large screen terminal on a small screen is time consuming and cumbersome task because there are many irrelevant content parts which are to be scrolled or there are advertisements, etc. Here main concern is e-business users. To overcome such issues the source code of a web page is organized in tree data-structure. In this paper we are arranging each and every main heading as a root node and all the content of this heading as a child node of the logical structure. Using this structure, we regenerate a web-page automatically according to SST size. Background:: DOM and VIPS algorithms are the main background techniques which are supporting the current research. Objective:: To restructure a web page in a more user friendly and content presenting format. Method Backtracking:: Method Backtracking: Results:: web page heading queue generation. Conclusion:: Concept of logical structure supports every SST.

MackDroid - An Android based Application to monitor devices

2016 ◽  
Vol 9 ◽  
pp. 1
Author(s):  
Maaz Sirkhot ◽  
Ekta Sirwani ◽  
Aishwarya Kourani ◽  
Akshit Batheja ◽  
Kajal Jethanand Jewani
Keyword(s):  
Operating System ◽  
Open Source ◽  
Vital Role ◽  
Mobile Users ◽  
Android Application ◽  
Web Page ◽  
Technological World ◽  
Monitoring Service ◽  
User Friendly

In this technological world, smartphones can be considered as one of the most far-reaching inventions. It plays a vital role in connecting people socially. The number of mobile users using an Android based smartphone has increased rapidly since last few years resulting in organizations, cyber cell departments, government authorities feeling the need to monitor the activities on certain targeted devices in order to maintain proper functionality of their respective jobs. Also with the advent of smartphones, Android became one of the most popular and widely used Operating System. Its highlighting features are that it is user friendly, smartly designed, flexible, highly customizable and supports latest technologies like IoT. One of the features that makes it exclusive is that it is based on Linux and is Open Source for all the developers. This is the reason why our project Mackdroid is an Android based application that collects data from the remote device, stores it and displays on a PHP based web page. It is primarily a monitoring service that analyzes the contents and distributes it in various categories like Call Logs, Chats, Key logs, etc. Our project aims at developing an Android application that can be used to track, monitor, store and grab data from the device and store it on a server which can be accessed by the handler of the application.

scholarly journals PPM1G promotes the progression of hepatocellular carcinoma via phosphorylation regulation of alternative splicing protein SRSF3

2021 ◽  
Vol 12 (8) ◽  
Author(s):  
Dawei Chen ◽  
Zhenguo Zhao ◽  
Lu Chen ◽  
Qinghua Li ◽  
Jixue Zou ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Alternative Splicing ◽  
Protein Function ◽  
Vital Role ◽  
Normal Tissues ◽  
Mechanistic Analysis ◽  
Highly Correlated ◽  
Splicing Patterns

AbstractEmerging evidence has demonstrated that alternative splicing has a vital role in regulating protein function, but how alternative splicing factors can be regulated remains unclear. We showed that the PPM1G, a protein phosphatase, regulated the phosphorylation of SRSF3 in hepatocellular carcinoma (HCC) and contributed to the proliferation, invasion, and metastasis of HCC. PPM1G was highly expressed in HCC tissues compared to adjacent normal tissues, and higher levels of PPM1G were observed in adverse staged HCCs. The higher levels of PPM1G were highly correlated with poor prognosis, which was further validated in the TCGA cohort. The knockdown of PPM1G inhibited the cell growth and invasion of HCC cell lines. Further studies showed that the knockdown of PPM1G inhibited tumor growth in vivo. The mechanistic analysis showed that the PPM1G interacted with proteins related to alternative splicing, including SRSF3. Overexpression of PPM1G promoted the dephosphorylation of SRSF3 and changed the alternative splicing patterns of genes related to the cell cycle, the transcriptional regulation in HCC cells. In addition, we also demonstrated that the promoter of PPM1G was activated by multiple transcription factors and co-activators, including MYC/MAX and EP300, MED1, and ELF1. Our study highlighted the essential role of PPM1G in HCC and shed new light on unveiling the regulation of alternative splicing in malignant transformation.

scholarly journals Growth Promotion or Osmotic Stress Response: How SNF1-Related Protein Kinase 2 (SnRK2) Kinases Are Activated and Manage Intracellular Signaling in Plants

Plants ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1443
Author(s):  
Yoshiaki Kamiyama ◽  
Sotaro Katagiri ◽  
Taishi Umezawa
Keyword(s):  
Protein Kinase ◽  
Plant Growth ◽  
Osmotic Stress ◽  
Protein Function ◽  
Intracellular Signaling ◽  
Growth Promotion ◽  
Research Field ◽  
Dependent Manner ◽  
Related Protein ◽  
Wide Range

Reversible phosphorylation is a major mechanism for regulating protein function and controls a wide range of cellular functions including responses to external stimuli. The plant-specific SNF1-related protein kinase 2s (SnRK2s) function as central regulators of plant growth and development, as well as tolerance to multiple abiotic stresses. Although the activity of SnRK2s is tightly regulated in a phytohormone abscisic acid (ABA)-dependent manner, recent investigations have revealed that SnRK2s can be activated by group B Raf-like protein kinases independently of ABA. Furthermore, evidence is accumulating that SnRK2s modulate plant growth through regulation of target of rapamycin (TOR) signaling. Here, we summarize recent advances in knowledge of how SnRK2s mediate plant growth and osmotic stress signaling and discuss future challenges in this research field.

scholarly journals BloodGen3Module: Blood transcriptional module repertoire analysis and visualization using R

2021 ◽  
Author(s):  
Darawan Rinchai ◽  
Jessica Roelands ◽  
Mohammed Toufiq ◽  
Wouter Hendrickx ◽  
Matthew C Altman ◽  
...  
Keyword(s):  
Transcript Abundance ◽  
R Package ◽  
Supplementary Information ◽  
Illustrative Case ◽  
Bioinformatic Tools ◽  
Transcriptional Module ◽  
Wide Range ◽  
Downstream Analysis ◽  
Computing Module ◽  
Parallel Workflow

Abstract Motivation We previously described the construction and characterization of generic and reusable blood transcriptional module repertoires. More recently we released a third iteration (“BloodGen3” module repertoire) that comprises 382 functionally annotated gene sets (modules) and encompasses 14,168 transcripts. Custom bioinformatic tools are needed to support downstream analysis, visualization and interpretation relying on such fixed module repertoires. Results We have developed and describe here a R package, BloodGen3Module. The functions of our package permit group comparison analyses to be performed at the module-level, and to display the results as annotated fingerprint grid plots. A parallel workflow for computing module repertoire changes for individual samples rather than groups of samples is also available; these results are displayed as fingerprint heatmaps. An illustrative case is used to demonstrate the steps involved in generating blood transcriptome repertoire fingerprints of septic patients. Taken together, this resource could facilitate the analysis and interpretation of changes in blood transcript abundance observed across a wide range of pathological and physiological states. Availability The BloodGen3Module package and documentation are freely available from Github: https://github.com/Drinchai/BloodGen3Module Supplementary information Supplementary data are available at Bioinformatics online.

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