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Related Concept Videos

Allosteric Proteins-ATCase01:19

Allosteric Proteins-ATCase

Binding sites linkages can regulate a protein's function.  For example, enzyme activity is often regulated through a feedback mechanism where the end product of the biochemical process serves as an inhibitor.
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to  N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis pathway,...
Cooperative Allosteric Transitions01:58

Cooperative Allosteric Transitions

Cooperative allosteric transitions can occur in multimeric proteins, where each subunit of the protein has its own ligand-binding site. When a ligand binds to any of these subunits, it triggers a conformational change that affects the binding sites in the other subunits; this can change the affinity of the other sites for their respective ligands. The ability of the protein to change the shape of its binding site is attributed to the presence of a mix of flexible and stable segments in the...
Cooperative Allosteric Transitions01:58

Cooperative Allosteric Transitions

Cooperative allosteric transitions can occur in multimeric proteins, where each subunit of the protein has its own ligand-binding site. When a ligand binds to any of these subunits, it triggers a conformational change that affects the binding sites in the other subunits; this can change the affinity of the other sites for their respective ligands. The ability of the protein to change the shape of its binding site is attributed to the presence of a mix of flexible and stable segments in the...
Cooperative Allosteric Transitions01:58

Cooperative Allosteric Transitions

Cooperative allosteric transitions can occur in multimeric proteins, where each subunit of the protein has its own ligand-binding site. When a ligand binds to any of these subunits, it triggers a conformational change that affects the binding sites in the other subunits; this can change the affinity of the other sites for their respective ligands. The ability of the protein to change the shape of its binding site is attributed to the presence of a mix of flexible and stable segments in the...
Ligand Binding and Linkage00:49

Ligand Binding and Linkage

Allosteric proteins have more than one ligand binding site; the binding of a ligand to any of these sites influences the binding of ligands to the other sites. When a protein is allosteric, its binding sites are called coupled or linked.  In the case of enzymes, the site that binds to the substrate is known as the active site and the other site is known as the regulatory site. When a ligand binds to the regulatory site, this leads to conformational changes in the protein that can influence the...
Allosteric Regulation01:08

Allosteric Regulation

Allosteric regulation of enzymes occurs when the binding of an effector molecule to a site that is different from the active site causes a change in the enzymatic activity. This alternate site is called an allosteric site, and an enzyme can contain more than one of these sites. Allosteric regulation can either be positive or negative, resulting in an increase or decrease in enzyme activity. Most enzymes that display allosteric regulation are metabolic enzymes involved in the degradation or...

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Quantifying Correlations Between Allosteric Sites in Thermodynamic Ensembles.

Christopher L McClendon1, Gregory Friedland, David L Mobley

  • 1University of California San Francisco, Graduate Group in Biophysics and Department of Pharmaceutical Chemistry.

Journal of Chemical Theory and Computation
|February 18, 2010
PubMed
Summary
This summary is machine-generated.

We developed MutInf, a novel method to detect correlated protein motions using molecular dynamics simulations. This tool identifies allosteric sites by analyzing residue correlations, aiding in the discovery of new therapeutic targets.

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Published on: November 21, 2017

Area of Science:

  • Biophysics
  • Computational Biology
  • Structural Biology

Background:

  • Allostery involves altered protein function at distant sites, often via correlated motions.
  • Correlated motions can occur without significant conformational changes, posing a challenge for traditional methods.
  • Identifying these subtle correlated motions is key to understanding allosteric regulation.

Purpose of the Study:

  • To introduce a novel computational method, "MutInf", for identifying statistically significant correlated motions in proteins.
  • To apply this method to uncover mechanisms of cooperative small molecule binding in human interleukin-2.
  • To provide a robust tool for discovering novel or "orphan" allosteric sites.

Main Methods:

  • Utilized equilibrium molecular dynamics simulations.
  • Analyzed both backbone and sidechain motions using internal coordinates.
  • Quantified correlated motions with a mutual information metric, extended for multiple simulations and statistical filtering.

Main Results:

  • Identified clusters of correlated residues in human interleukin-2 from 50 ns simulations.
  • Highlighted known cooperative small-molecule binding sites with strong inter-site correlations.
  • Revealed correlations mediated by both hydrophobic core and dynamic polar networks.

Conclusions:

  • The MutInf method robustly identifies correlated protein motions and allosteric sites.
  • Correlated motions in interleukin-2 involve both hydrophobic and polar interaction networks.
  • MutInf is a valuable tool for discovering novel allosteric sites in proteins of biological and therapeutic significance.