How does proteins plus work?
The main objective during the development of Proteins Plus was to create a general workflow to access and preprocess structural data for all kinds of life science research. The resulting workflow starts with the selection of a PDB ID or the upload of a custom PDB file and optionally a ligand file in SD format as input.
What is a protein-protein interaction?
Protein-protein interactions (PPIs) form the basis for regulatory pathways in a cell and are thus involved in all major biological processes like metabolism, cell division or apoptosis. In this video you will learn how to discriminate PPIs from crystal artifacts.
How to characterize the different types of proteins plus?
The prediction tool HyPPI underlying Proteins Plus discriminates biological complexes and crystal artefacts. The most promising descriptors we found to characterize the different PPIs are the hydrophobic binding energy and the proportion of the interface ratios (IFquotient).
What is the entry point to proteins Plus service?
The entry point to the Proteins Plus service is in many cases a publicly available structure from the PDB whose PDB code is not necessarily known to the user. To overcome this issue, a keyword search combined with a small number of quality filters was introduced.
What does protein interact with?
Proteins bind to each other through a combination of hydrophobic bonding, van der Waals forces, and salt bridges at specific binding domains on each protein. These domains can be small binding clefts or large surfaces and can be just a few peptides long or span hundreds of amino acids.
What is an example of a Protein Protein interaction?
These interactions between proteins are dependent on highly specific binding between proteins to ensure efficient electron transfer. Examples: mitochondrial oxidative phosphorylation chain system components cytochrome c-reductase / cytochrome c / cytochrome c oxidase; microsomal and mitochondrial P450 systems.
What is protein-ligand interaction?
Interactions. The protein-ligand complex is a reversible non-covalent interaction between two biological (macro)molecules. In non-covalent interactions there is no sharing of electrons like in covalent interactions or bonds.
What are three common interactions of protein molecules with other?
Interactions are driven by the formation of non-covalent bonds, i.e. hydrogen bonds, ionic bonds, van der Waals forces and/or hydrophobic interactions.
How many protein-protein interactions are there?
The largest of its kind, the Human Reference Interactome (HuRI) map charts 52,569 interactions between 8,275 human proteins, as described in a study published in Nature.
How do you test protein-protein interactions?
Chemical cross-linking followed by high mass MALDI mass spectrometry can be used to analyze intact protein interactions in place before trying to isolate/identify interacting proteins. This method detects interactions among non-tagged proteins and is available from CovalX.
How do ligands bind to proteins?
A ligand is a small molecule that is able to bind to proteins by weak interactions such as ionic bonds, hydrogen bonds, Van der Waals interactions, and hydrophobic effects. In some cases, a ligand also serves as a signal triggering molecule. A ligand can be a substrate inhibitor, activator or a neurotransmitter.
What is ligand receptor interaction?
Receptor-ligand interactions are a major class of protein-protein interactions and play an important role in many biological processes such as metabolism, neurotransmission and cellular signal transduction pathways.
How do you study protein-ligand interactions?
X-ray crystallography is a powerful technique for studying protein-ligand interactions. Advances in techniques have meant that it is now possible to routinely determine the structures of ligand complexes in the majority of cases where crystallization conditions and protein structures are already known.
Do proteins interact with enzymes?
Every day, trillions upon trillions of chemical reactions occur in our body to make essential metabolic processes occur. Enzymes are proteins that act upon substrate molecules and decrease the activation energy necessary for a chemical reaction to occur by stabilizing the transition state.
How do proteins bond to other molecules?
Within a protein, multiple amino acids are linked together by peptide bonds, thereby forming a long chain. Peptide bonds are formed by a biochemical reaction that extracts a water molecule as it joins the amino group of one amino acid to the carboxyl group of a neighboring amino acid.
How do proteins interact with DNA?
Proteins interact with DNA through electrostatic interactions (salt bridges), dipolar interactions (hydrogen bonding, H-bonds), entropic effects (hydrophobic interactions) and dispersion forces (base stacking).
How are protein-protein interactions modeled?
Protein-protein interaction networks are commonly modeled via graphs, whose nodes represent proteins and whose edges, that are undirected and possibly weighted, connect pairs of interacting proteins. Edge weights may be used to incorporate reliability information associated to the corresponding interactions.
What is the protein-protein interaction network (STRING)?
From protein–protein interaction network (STRING) ( Fig. 25.5 ), network indicated that the unique proteins of DM2R related with insulin signaling. Normally, insulin inhibits glycogenolysis and gluconeogenesis in liver. Akt is one of the major signaling molecules of insulin signaling pathway. The downstream of Akt signaling involved G6Pase and PEPCK, a critical enzyme for glycogenolysis and gluconeogenesis, respectively. To propose the effect of purple rice bran, mRNA expression levels of genes involving in insulin signaling ( Akt, G6Pase, and PEPCK) were measured.
What is the Akt pathway?
Akt is one of the major signaling molecules of insulin signaling pathway. The downstream of Akt signaling involved G6Pase and PEPCK, a critical enzyme for glycogenolysis and gluconeogenesis, respectively.
What is a candidate PPI network?
The candidate PPI network can be depicted as a dynamic system in which interactive proteins and mRNA are considered as inputs of the system and protein activities as outputs of the system. All proteins in the candidate PPI network can be considered as target proteins. For a target protein p in the candidate PPI network with N interacting proteins, a dynamic model of the protein’s activity can be represented as follows:
What is PPI network?
Protein-protein interaction (PPI) networks, in contrast, have used network analysis extensively to identify the most essential proteins for the parasite. As their name suggests, PPI link proteins that are known to be correlated through some interaction.
What is PPI in biology?
Protein–protein interaction (PPI) networks describe physical interactions between proteins, taking place to mediate the assembly of proteins into protein complexes, or e.g., mediating signaling/regulation and transport events in the cell.
Is a more complex model more suitable for protein-protein interactions?
It is important to point out that, since protein-protein interactions are often obtained from protein complex detection and not really as binary interactions, a more complex model may be more suitable for the representation of protein-protein interaction networks. In fact, the use of hyper-graphs, instead of simple graphs, ...
What are protein domains?
Proteins often utilize small folded domains for interactions with other proteins. The basic hypothesis guiding our research is that by mimicking these domains we can modulate the function of a particular protein-protein interaction with metabolically stable synthetic molecules. This presentation will discuss synthetic approaches to develop protein domain mimics as modulators of intracellular protein-protein interactions, with the Ras-Sos interaction as a case study.
What is PPI in drug discovery?
Protein-Protein interactions (PPI) have great potential as therapeutic targets but are currently one of the most challenging areas in drug discovery partly due to specific structural features of PPI modulating ligands. This talk will focus on the lessons Asinex has learned and its unique approach to address the problem using a “compound-to-target” strategy, our design of lead like PPI ligands, and lead optimization strategy. We will also briefly introduce a case study in PPI drug discovery.
Who is Michelle Arkin?
Michelle Arkin, Ph.D., Associate Professor, Pharmaceutical Chemistry, University of California, San Francisco. Protein-protein interactions and allosterically regulated enzymes have been challenging but important targets for probe- and drug discovery, especially in the inflammation field.
What is the role of ITK in inflammatory diseases?
Interleukin-2-inducible T-cell kinase (ITK) is a critical mediator of T cell signaling and hen ce an attractive target for T-cell mediated inflammatory diseases. We have discovered allosteric Type III inhibitors of ITK that also bind to its ATP site. Through classical medicinal chemistry approaches, we have been successful in further optimization of these compounds that leads to selective inhibition of the inactive form of ITK. We will describe how an integrated biophysical technology platform coupled with classical enzymology studies enabled the discovery of allosteric ITK inhibitors.
What is protein plus?
Proteins Plus presents a unified interface for various structure-based modeling tools. It makes the installation of large modeling software packages for an initial inspection of protein structural data dispensable. Therefore, the server is of special interest to life scientists with an occasional need to work with protein structures. The integrated NGL web viewer gives a first impression of the input structure and the calculated results. Thanks to the caching system, users can also share the results or check them later without any further calculation. With currently six tools, the unified easy-to-use interface and the generalized workflow, the Proteins Plus web server is a valuable resource for structure-based life science research. For the future, we plan to extend its functionality by additional modeling techniques and further improve its usability, e.g. by predefined use case parameterizations and by a pipeline functionality which allows to use previously calculated results as input for other integrated tools.
Why are PPIs important?
PPIs play key roles in biological regulatory pathways. Therefore, they are of central importance for the understanding of biological processes. Furthermore, they are of special interest for the development of small molecule modulators and lately received more attention in drug discovery ( 45 – 47 ). The PDB contains a substantial amount of structural data related to protein–protein complexes. However, the asymmetric unit (the smallest structure that cannot be recreated using symmetry operations) deposited in the PDB file is not necessarily composed of a biological-relevant protein–protein complex. The protein–protein complex might only be due to crystallization conditions (crystal artefact) or the biological-relevant complex must be generated by applying symmetry operations first. Since experimental methods for the determination of the oligomeric state of a complex are costly and time-consuming, it is of interest to develop an automated discrimination of biological complexes (permanent or transient) and crystal artefacts. Diverse methods exist which try to predict PPIs based on the computation of free energies or classification models based on physico-chemical and geometrical descriptors, e.g. PQS ( 48 ), NOXclass ( 49 ), EPIC ( 50 ), PISA ( 51 ), DiMoVo ( 52 ), CRK ( 53 ), OringPV ( 54 ), IPAC ( 55) or IChemPIC ( 56 ). Most of those methods achieve high accuracies of 85–97%. However, they use a large amount of descriptors to discriminate those complexes (22–213 descriptors).
What is protein plus?
Due to the increasing amount of publicly available protein structures searching, enriching and investigating these data still poses a challenging task. The Proteins Plus web service ( https://proteins.plus) offers a broad range of tools addressing these challenges. The web interface to the tool collection focusing on protein–ligand interactions has been geared towards easy and intuitive access to a large variety of functionality for life scientists. Since our last publication, the Proteins Plus web service has been extended by additional services as well as it has undergone substantial infrastructural improvements. A keyword search functionality was added on the start page of Proteins Plus enabling users to work on structures without knowing their PDB code. The tool collection has been augmented by three tools: StructureProfiler validates ligands and active sites using selection criteria of well-established protein–ligand benchmark data sets, WarPP places water molecules in the ligand binding sites of a protein, and METALizer calculates, predicts and scores coordination geometries of metal ions based on surrounding complex atoms. Additionally, all tools provided by Proteins Plus are available through a REST service enabling the automated integration in structure processing and modeling pipelines.
Why can't a ligand be converted to a potential water position?
Due to close contact with other ligand or protein atoms, some of the interaction surface may not be available and thus cannot be converted into potential water positions. Finally, all potential water positions that are position-optimized and merged in a self-assembling procedure.