Allosteric regulation. Medical search. Frequent questions

Allosteric modulators of sigma-1 receptor (Sig1R) are described as compounds that can increase the activity of some Sig1R ligands that compete with (+)-pentazocine, one of the classic prototypical ligands that binds to the orthosteric Sig1R binding site. (frontiersin.org)
Different experimental approaches have been used to describe and validate the activity of allosteric modulators of Sig1R. (frontiersin.org)
Accumulating evidence suggests that allosteric Sig1R modulators affect processes involved in the pathophysiology of depression, memory and cognition disorders as well as convulsions. (frontiersin.org)
This review will focus on the description of selective and non-selective allosteric modulators of Sig1R, including molecular structure properties and pharmacological activity both in vitro and in vivo , with the aim of providing the latest overview from compound discovery approaches to eventual clinical applications. (frontiersin.org)
Thus, far no allosteric modulators of Sig2R have been reported. (frontiersin.org)
However, the notion that allosteric modulators of Sig1R are identified is an additional argument for the "receptor" view of Sig1R. (frontiersin.org)
The binding of allosteric modulators to a target protein induces a conformational change in the protein structure and changes the activity of orthosteric ligands ( Figure 1 ). (frontiersin.org)
Allosteric modulators can be positive or negative effectors (PAMs or NAMs, respectively). (frontiersin.org)
The definition of allosteric Sig1R modulators might be artificial due to a lack of information on the orthosteric binding site for Sig1R. (frontiersin.org)
Thus, allosteric modulators of Sig1R are described as compounds that can increase the activity of Sig1R ligands that compete with [ 3 H](+)-pentazocine for binding to Sig1R. (frontiersin.org)
Allosteric modulators seldom resemble the substrate or product of the enzyme. (flashcardmachine.com)
We have also analyzed mechanisms by which kinase drugs and allosteric Hsp90 modulators that may act synergistically and exert their pharmacological effect by depriving the client kinase of access to the molecular chaperone. (utoronto.ca)
However, direct use of 5-HT 2C receptor positive allosteric modulators in precision medicine is currently being studied. (medscape.com)

Ensemble models of allosteric regulation enumerate an allosteric system's statistical ensemble as a function of its potential energy function, and then relate specific statistical measurements of allostery to specific energy terms in the energy function (such as an intermolecular salt bridge between two domains). (wikipedia.org)
Integration of computational systems biology and machine learning analysis of the Hsp90 interactions with oncogenic kinase mutants is then used to construct models of allosteric regulation of oncogenic proteins by molecular chaperones in signaling cascades. (utoronto.ca)

In biochemistry, allosteric regulation (or allosteric control) is the regulation of an enzyme by binding an effector molecule at a site other than the enzyme's active site. (wikipedia.org)
Allosteric regulation is also particularly important in the cell's ability to adjust enzyme activity. (wikipedia.org)
This model studies a naturally occurring allosteric reaction: the first step in the pyrimidine synthesis, catalyzed by the allosteric enzyme aspartate carbamoyltransferase (ATCase). (wolfram.com)
Exploring how ATCase flows between states (tense, relaxed and enzyme-substrate complex) over time based on modifiers and substrate can assist in grasping the concept of allosteric regulation. (wolfram.com)
Notably, a form of enzyme regulation (called allostery) utilises ligand binding at a site other than the active site to effect changes in catalytic rate. (waikato.ac.nz)
In allosteric deactivation a regulatory molecule binds to a site other than the active site, resulting in a change in enzyme shape that allows the active site to bind substrate. (nursingdons.com)
In addition, they have among the most complex allosteric regulations of any enzyme system. (lu.se)
We are also determining the structure of other class III RNRs which have overall activity regulation (the T4 enzyme does not), as well as of mutants of the T4 RNR which affect the catalytic mechanism and the allosteric regulation. (lu.se)
Understanding Abl's regulation is important because a mutant form of the enzyme (Bcr-Abl) is over activated in chronic myelogenous leukemia and other cancers. (stjude.org)
The Abl enzyme controls this switching through a process called allosteric regulation in which a part of the molecule distant from the molecule's on-off switch or kinase domain somehow inhibits or activates Abl. (stjude.org)
The different conformations of Arg80 coupled to rearrangements in the quaternary structure imply that this residue plays a major role in regulation of the enzyme and in communication between subunits. (rcsb.org)

Allosteric regulation may be facilitated by the evolution of large-scale, low-energy conformational changes, which enables long-range allosteric interaction between distant binding sites. (wikipedia.org)

First, drugs targeting allosteric sites can modulate the structure of receptors, and thus adjust certain pharmacological responses. (wolfram.com)

Effectors that enhance the protein's activity are referred to as allosteric activators, whereas those that decrease the protein's activity are called allosteric inhibitors. (wikipedia.org)
In addition, we conducted a large fragment screening campaign against NendoU and identified several new allosteric sites that could be targeted for the development of new inhibitors. (lu.se)
This relatively unexplored therapeutic potential and the putative advantages of allosteric drugs over classical active-site inhibitors fuel the attention allosteric-drug research is receiving at present. (biomedcentral.com)
An important factor fueling interest in allosteric drugs consists in their characteristic advantages compared to traditional active-site inhibitors. (biomedcentral.com)
LCFA-CoA esters promote their own oxidation by acting as allosteric inhibitors of acetyl-CoA carboxylase, which reduces the production of malonyl-CoA and relieves inhibition of carnitine palmitoyl-transferase 1, thereby promoting LCFA-CoA transport into the mitochondria for β-oxidation2-6. (mcmaster.ca)

We also explored the possibility of NendoU assembling into larger supramolecular structures and proposed a mechanism for allosteric regulation. (lu.se)
Indeed, they provide a possible mechanism of allosteric regulation, which unlocks one catalytic groove when the second groove is inhibited by the double strand region of tRNA. (cnr.it)
Allosteric conversion of partial to full agonism may be a general mechanism for reversibly scaling the efficacy of GABA A receptors to endogenous partial agonists. (jneurosci.org)
Network-defined modularity of interacting components and cross-talk in signal transduction networks are quantified through molecular mechanism of allosteric regulation. (utoronto.ca)

To summarize: subunits need not exist in the same conformation molecules of substrate bind via induced-fit protocol conformational changes are not propagated to all subunits The morpheein model of allosteric regulation is a dissociative concerted model. (wikipedia.org)
In allosteric activation a regulatory molecule binds to the active site, allowing substrate binding. (nursingdons.com)
More recently we have probed the allosteric regulation of class II and class III RNRs by solving the structures of complexes with several combinations of allosteric effector and substrate [2,5]. (lu.se)

Number of selective Sig1R and Sig2R ligands have been described confirming significant differences in the pharmacological regulation of these subtypes. (frontiersin.org)
In this article, we describe a simple computational approach, based on the effect allosteric ligands exert on protein flexibility upon binding, to predict the existence and position of allosteric sites on a given protein structure. (biomedcentral.com)
We also analyzed four biological examples in detail, revealing that this simple coarse-grained methodology is able to capture the effects triggered by allosteric ligands already described in the literature. (biomedcentral.com)

The site to which the effector binds is termed the allosteric site or regulatory site. (wikipedia.org)
This is in reference to the fact that the regulatory site of an allosteric protein is physically distinct from its active site. (wikipedia.org)
To that end, we present a theory of allosteric transcriptional regulation using the Monod-Wyman-Changeux model which applies to a variety of regulatory architectures. (aps.org)
Allosteric interactions of the Hsp90 with cochaperones and protein kinase clients can determine regulatory mechanisms and cellular functions of many signaling proteins and cascades. (utoronto.ca)
Biophysical modeling of allosteric regulation in the protein kinases has offered additional insights into organizing principles of kinase activation by molecular chaperones that may be orchestrated by a cross-talk between key regulatory regions. (utoronto.ca)
A first step to harness the regulatory potential and versatility of allosteric sites, in the context of drug-discovery and design, would be to detect or predict their presence and location. (biomedcentral.com)
The researchers' experiments explored in detail how the region of Abl called the allosteric regulatory module interacted with the kinase domain to control it. (stjude.org)

Allosteric modulation is used to alter the activity of molecules and enzymes in biochemistry and pharmacology. (wikipedia.org)
It is even more intriguing to consider the potential plasticity of allosteric modulation given the observation of agonist-dependent functional properties of GABA A receptors. (jneurosci.org)
However, for most allosteric proteins identified to date the mechanistic details of allosteric modulation are not yet well understood. (biomedcentral.com)

β1 subunit mutations that inhibit AMPK activation by the small-molecule activator A769662, which binds to the allosteric drug and metabolite site, also inhibit activation by LCFA-CoAs. (mcmaster.ca)

Our results highlight the importance of flexible linkers in regulating multidomain chromatin binding proteins and point to divergent evolution of their regulation. (edu.sa)
By querying the literature and a recently available database of allosteric sites, we gathered 213 allosteric proteins with structural information that we further filtered into a non-redundant set of 91 proteins. (biomedcentral.com)
Its performance has been demonstrated using a newly curated non-redundant set of 91 proteins with reported allosteric properties. (biomedcentral.com)

Alternative splicing and allosteric regulation modulate the chromatin binding of UHRF1. (edu.sa)

Allosteric sites allow effectors to bind to the protein, often resulting in a conformational change and/or a change in protein dynamics. (wikipedia.org)
Allosteric drugs bind to sites which are usually less conserved evolutionarily as compared to orthosteric sites. (nih.gov)
There is now a new generation of drugs that bind to the allosteric pocket to inhibit its activity,' he said. (stjude.org)

While many of the mutations block Gleevec from plugging into the kinase domain, others appear to interfere with the allosteric regulation. (stjude.org)
These could be combined with Gleevec to overcome allosteric mutations to shift Abl into an inhibited state. (stjude.org)

The results of biophysical and computational systems biology analyses combined with proteomics experiments have been integrated into a graph-based network model of allosteric regulation. (utoronto.ca)

The allostery landscape model introduced by Cuendet, Weinstein, and LeVine allows for the domains to have any number of states and the contribution of a specific molecular interaction to a given allosteric coupling can be estimated using a rigorous set of rules. (wikipedia.org)
Allostery is one of the most powerful and common ways of regulation of protein activity. (biomedcentral.com)
Tight regulation of these processes is fundamental in all kingdoms of life and allostery represents one of the most commmon and powerful means of modulating protein activity[ 1 ]. (biomedcentral.com)
Allostery can be defined as the regulation of a protein's function by binding of an effector molecule at a site which is not the active site. (biomedcentral.com)

These results agree with the current view that allosteric mechanisms are in many cases governed by changes in protein dynamics caused by ligand binding. (biomedcentral.com)
At present, allosteric phenomena are being intensively studied for their potential as target mechanisms for the development of new classes of therapeutics[ 4 ]. (biomedcentral.com)

Allosteric regulation is a prime drug target because it reduces the risk of overdose and side effects and can be used to fine-tune pharmacological processes. (wolfram.com)
Finally, the development of allo-network drugs, which are allosteric drugs acting indirectly on the neighborhood of the pharmacological target in protein-protein interaction or signaling networks, is described. (nih.gov)

Here we show in atomistic detail how the human β2-adrenergic receptor (β2AR) - a prototypical G protein-coupled receptor - is modulated by cholesterol in an allosteric fashion. (helsinki.fi)
GLP-1 is a physiologic regulator of appetite and calorie intake, and the GLP-1 receptor is present in several areas of the brain involved in appetite regulation. (medscape.com)

Understanding allosteric regulation is essential when studying medicines, because allosteric sites can be a prime drug target. (wolfram.com)

The allosteric interactions and regulation of molecular chaperones and protein kinases allow for molecular communication and event coupling in signal transduction networks. (utoronto.ca)

Activation of AMPK by LCFA-CoA esters requires the allosteric drug and metabolite site formed between the α-subunit kinase domain and the β-subunit. (mcmaster.ca)

This mini-hot-topic issue of CTMC showcases some successes and challenges of allosteric drug development through the examples of seventransmembrane (GPCR), AMPA, NMDA and metabotropic glutamate receptors, as well as the morpheein model of allosterism involved in inherent metabolic errors. (nih.gov)

There is evidence that lipids can be allosteric regulators of membrane protein structure and activation. (helsinki.fi)
These components are integrated through long-range communication relays, with lipids playing an essential role in regulation. (utmb.edu)

This work establishes a central role for the PIF-pocket on the regulation of PKCζ and allows us to envisage development of drugs targeting the PIF-pocket that can either activate or inhibit AGC kinases. (hal.science)

We introduce a simple computational approach to predict the presence and position of allosteric sites in a protein based on the analysis of changes in protein normal modes upon the binding of a coarse-grained ligand at predicted cavities. (biomedcentral.com)

Allosteric regulation is the regulation of protein activity by binding an effector molecule at a site other than the orthosteric or active site of a protein ( Figure 1 ). (frontiersin.org)
As bioactive molecule, ceramide is involved in the regulation of many cellular processes. (elifesciences.org)
Such regulation would involve pushing the Abl molecule toward either the inhibited or activated shape, he said. (stjude.org)

For example, allosteric sites tend to be under lower sequence-conservation pressure than active sites, facilitating the design of highly specific drugs and reducing the risks of toxicity or side-effects[ 5 - 7 ]. (biomedcentral.com)

Which statement most accurately explains how allosteric regulation can change an enzyme's activity? (nursingdons.com)
Notably, we found that the C1 domain allosterically inhibits PKCζ activity and verified an allosteric communication between the PIF-pocket of atypical PKCs and the binding site of the C1 domain. (hal.science)

Furthermore, we implemented an approach that achieves 65% positive predictive value in identifying allosteric sites within the set of predicted cavities of a protein (stricter parameters set, 0.22 sensitivity), by combining the current analysis on dynamics with previous results on structural conservation of allosteric sites. (biomedcentral.com)

Regulation of CpG-induced immune activation by suppressive oligodeoxynucleotides. (metu.edu.tr)
Ultrasensitive regulation of anapleurosis via allosteric activation of PEP carboxylase. (princeton.edu)

Here we report a new level of regulation wherein LCFA-CoA esters per se allosterically activate AMP-activated protein kinase (AMPK) β1-containing isoforms to increase fatty acid oxidation through phosphorylation of acetyl-CoA carboxylase. (mcmaster.ca)

Here, we performed enzymatic characterization of NendoU in its monomeric and hexameric form, showing that hexamers are allosteric enzymes with a positive cooperative index, and with no influence of. (lu.se)

This method of analysis is useful when aiming to understand the properties of allosteric regulation. (wolfram.com)

To understand the allosteric regulation, crystal structures were determined for S. solfataricus UPRTase in complex with UMP and with UMP and the allosteric inhibitor CTP. (rcsb.org)

Many allosteric effects can be explained by the concerted MWC model put forth by Monod, Wyman, and Changeux, or by the sequential model (also known as the KNF model) described by Koshland, Nemethy, and Filmer. (wikipedia.org)
Second, potential toxic effects can be avoided, since a limitation in cooperavitity between the allosteric drug and an orthosterically binding ligand will avoid overdosing. (wolfram.com)

Calcium (Ca 2+ ) signaling plays an important role in the regulation of many cellular functions. (frontiersin.org)

The required oligomer disassembly step differentiates the morpheein model for allosteric regulation from the classic MWC and KNF models. (wikipedia.org)
Ensemble models like the ensemble allosteric model and allosteric Ising model assume that each domain of the system can adopt two states similar to the MWC model. (wikipedia.org)

Allosteric regulations are a natural example of control loops, such as feedback from downstream products or feedforward from upstream substrates. (wikipedia.org)

Anatomy1

Organisms2

Chemicals and Drugs40

Analytical, Diagnostic and Therapeutic Techniques and Equipment11

Phenomena and Processes33

Information Science4

Health Care1

Modulators13

Models of allosteric regulation2

Enzyme11

Long-range allosteric1

Targeting allosteric sites1

Inhibitors5

Mechanism4

Substrate3

Ligands3

Regulatory7

Modulation3

Binds1

Proteins3

Modulate1

Bind3

Mutations2

Biophysical1

Allostery4

Mechanisms2

Pharmacological2

Receptor2

Understanding1

Molecular1

Kinase domain1

Receptors1

Lipids2

Inhibit1

Computational1

Molecule3

Drugs1

Activity2

Structural1

Activation2

Allosterically1

Positive1

Properties1

Structures1

Effects2

Important1

Model2

Control1