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Related Concept Videos

Allosteric Regulation01:08

Allosteric Regulation

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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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Enzyme Inhibition01:30

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Inhibitors are molecules that reduce enzyme activity by binding to the enzyme. In a normally functioning cell, enzymes are regulated by a variety of inhibitors. Drugs and other toxins can also inhibit enzymes. Some inhibitors bind to the enzyme’s active site, while others inhibit enzymatic activity by binding to other sites on the protein structure.
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Allosteric Proteins-ATCase01:19

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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.
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...
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Enzymes02:34

Enzymes

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Inside living organisms, enzymes act as catalysts for many biochemical reactions involved in cellular metabolism. The role of enzymes is to reduce the activation energies of biochemical reactions by forming complexes with its substrates. The lowering of activation energies favor an increase in the rates of biochemical reactions.
Enzyme deficiencies can often translate into life-threatening diseases. For example, a genetic abnormality resulting in the deficiency of the enzyme G6PD...
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Cooperative Allosteric Transitions01:58

Cooperative Allosteric Transitions

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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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Feedback Inhibition00:46

Feedback Inhibition

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Biochemical reactions are occurring constantly in cells, converting starting substances to different products, usually with the help of enzymes that speed the reactions. Without enzymes, it would take far too long for most reactions to occur to be useful to the cell!
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Updated: May 14, 2025

Bio-layer Interferometry for Measuring Kinetics of Protein-protein Interactions and Allosteric Ligand Effects
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Resistance to Allosteric Inhibitors.

Ian R Outhwaite1, Isabelle Kwan2, Ariel Leyte-Vidal3

  • 1Department of Pharmacological Sciences, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA.

Journal of Molecular Biology
|April 11, 2025
PubMed
Summary
This summary is machine-generated.

Allosteric inhibitors offer new therapeutic options but can also face resistance. Understanding these resistance mechanisms is key to developing resilient therapies, potentially through combination treatments.

Keywords:
allosterydrug resistanceenzymemechanism

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Area of Science:

  • Pharmacology
  • Molecular Biology
  • Drug Discovery

Background:

  • Allosteric inhibitors are valuable therapeutics overcoming resistance to orthosteric inhibitors.
  • However, resistance to allosteric inhibitors themselves can emerge, limiting long-term efficacy.

Purpose of the Study:

  • To review the molecular mechanisms of resistance to allosteric inhibitors.
  • To explore strategies for overcoming such resistance and developing more resilient therapies.

Main Methods:

  • Literature review of resistance mechanisms.
  • Analysis of molecular adaptations and signaling pathways involved in resistance.
  • Exploration of combination therapy strategies.

Main Results:

  • Resistance mechanisms include altered inhibitor binding, disrupted allosteric pathways, and off-target effects.
  • Drug efflux pumps and compensatory signaling pathways contribute to resistance.
  • Bitopic inhibitors and combination therapies show promise in mitigating resistance.

Conclusions:

  • Understanding diverse resistance mechanisms is critical for therapeutic development.
  • Combination strategies, including bitopic inhibitors, are essential for overcoming allosteric inhibitor resistance.
  • Further research is needed to design next-generation therapies resilient to resistance.