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Related Concept Videos

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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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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Ligand Binding and Linkage00:49

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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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Amplifying Signals via Enzymatic Cascade01:22

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When a ligand binds to a cell-surface receptor, the receptor's intracellular domain changes shape, which may either activate its enzyme function or allow its binding to other molecules. The initial signal is amplified by most signal transduction pathways. This means that a single ligand molecule can activate multiple molecules of a downstream target. Proteins that relay a signal are most commonly phosphorylated at one or more sites, activating or inactivating the protein. Kinases catalyze...
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Updated: Apr 30, 2026

Bio-layer Interferometry for Measuring Kinetics of Protein-protein Interactions and Allosteric Ligand Effects
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Biased Signaling as Allosteric Probe Dependence: Everything Old Is New Again.

Terry Kenakin1

  • 1Department of Pharmacology, University of North Carolina, School of Medicine, Chapel Hill, North Carolina 27599, United States.

Biochemistry
|April 29, 2026
PubMed
Summary

Biased signaling in G protein-coupled receptors (GPCRs) is a natural function, influenced by ligand-induced conformational changes. Understanding probe dependence and receptor state stabilization is key for drug selectivity and predicting in vitro to in vivo translation.

Keywords:
drug discoveryprobe dependent allosteryreceptor theory

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Area of Science:

  • Pharmacology
  • Biochemistry
  • Molecular Biology

Background:

  • G protein-coupled receptors (GPCRs) are crucial drug targets.
  • Ligand binding can induce conformational changes, leading to diverse signaling pathways.
  • Understanding GPCR signaling complexity is essential for drug development.

Purpose of the Study:

  • To explore biased signaling as an inherent function of GPCRs.
  • To discuss ligand-induced conformational changes and their impact on natural signaling.
  • To examine methods for detecting and measuring GPCR selectivity and state stabilization.

Main Methods:

  • Analysis of biased signaling through probe dependence.
  • Investigating conformational alterations induced by various ligands (agonists, antagonists, allosteric modulators).
  • Methods for detecting and quantifying selective stabilization of receptor states.

Main Results:

  • Biased signaling is a natural consequence of GPCR probe dependence.
  • Ligands can alter natural receptor signaling via conformational changes.
  • Selectivity is linked to intrinsic efficacy and stabilization of specific receptor states.

Conclusions:

  • Biased signaling is an intrinsic property of GPCRs.
  • Understanding conformational dynamics is vital for selective drug design.
  • Translating in vitro findings to in vivo systems requires careful consideration of receptor state stabilization.