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Related Concept Videos

Allosteric Regulation01:08

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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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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...
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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...
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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.
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The two-state receptor model explains a drug's interaction with receptors, such as G protein-coupled receptors and ligand-gated ion channels, to induce or inhibit a biological response. When no natural ligands are present, a receptor exists in an equilibrium of inactive (Ri) and active (Ra) conformations. The inactive form does not produce a response, while the active form generates a basal effect known as constitutive activity.
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Drug-receptor interaction describes the binding of receptors by drugs, but not all drug-receptor interactions result in activation and tissue response. For instance, the binding of agonists activates the receptor to generate a cellular reaction, while antagonists bind to receptors without causing their activation.
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Methods for the Discovery of Novel Compounds Modulating a Gamma-Aminobutyric Acid Receptor Type A Neurotransmission
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How Do Modulators Affect the Orthosteric and Allosteric Binding Pockets?

Chih-Jung Chen1,2, Chen Jiang1,2, Jiayi Yuan1,2

  • 1Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States.

ACS Chemical Neuroscience
|March 17, 2022
PubMed
Summary
This summary is machine-generated.

Allosteric modulators (AMs) minimally impact binding pockets in drug targets. This finding supports confident virtual screening and lead optimization for new medicines.

Keywords:
MCCSallosteric modulatordrug discovery

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Area of Science:

  • Pharmacology
  • Structural Biology
  • Computational Chemistry

Background:

  • Allosteric modulators (AMs) offer potential for selective drug action.
  • The precise effects of AMs on orthosteric and allosteric binding sites remain unclear.

Purpose of the Study:

  • To investigate the impact of AMs on the structural dynamics of orthosteric and allosteric binding pockets.
  • To assess the reliability of virtual screening and lead optimization in the presence of AMs.

Main Methods:

  • Analysis of 21 3D receptor-ligand and receptor-ligand-AM complex structures (GPCRs, ion channels, enzymes, transcription factors).
  • Utilized the Molecular Complex Characterizing System (MCCS) algorithm to quantify binding site residues and pocket changes.

Main Results:

  • Binding of AMs demonstrated minimal alterations to both orthosteric and allosteric binding pockets.
  • Key residues within binding sites were identified and characterized.

Conclusions:

  • AMs do not significantly induce conformational changes in binding pockets.
  • Accurate prediction of allosteric pockets enables reliable virtual screening and lead optimization for drug discovery.