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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 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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GPCR Desensitization01:12

GPCR Desensitization

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G protein-coupled receptor (GPCR) signaling plays a crucial role in cell functioning. GPCR desensitization is an equally essential process. It allows cells to respond to changing environments and regain sensitivity to new stimuli while preventing unnecessary stimulation when no longer needed. Prolonged exposure to stimuli leads to GPCR desensitization. It involves blocking the receptors from binding and activating additional G proteins. This inhibits activation of downstream effectors, thereby...
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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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Related Experiment Video

Updated: Jan 30, 2026

Monitoring GPCR-β-arrestin1/2 Interactions in Real Time Living Systems to Accelerate Drug Discovery
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A GPCR-G protein-β-arrestin megacomplex enabled by a versatile allosteric modulator.

Guodong He1, Qinxin Sun1, Xinyu Xu1

  • 1State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Pharmaceutical Sciences, Tsinghua University, Beijing, China; Beijing Frontier Research Center for Biological Structure, Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, Beijing, China.

Cell
|January 28, 2026
PubMed
Summary
This summary is machine-generated.

Researchers discovered atazanavir, a novel drug that stabilizes G protein-coupled receptor (GPCR) complexes. This compound enables sustained signaling and activates multiple GPCRs, offering new therapeutic development avenues.

Keywords:
G protein-coupled receptorsGPCR signaling transductionGPCR structuresGPCRscryo-EMdrug discoverymegacomplexpositive allosteric modulatorsustained signaling

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Area of Science:

  • Pharmacology
  • Molecular Biology
  • Drug Discovery

Background:

  • G protein-coupled receptors (GPCRs) are crucial drug targets, with about one-third of clinical drugs acting on them.
  • GPCR signaling traditionally involves separate G protein and β-arrestin pathways.
  • Novel strategies are needed to modulate GPCR activity for unique pharmacological outcomes.

Purpose of the Study:

  • To identify novel ligands that modulate GPCR activity through unique mechanisms.
  • To explore the stabilization of GPCR-G protein-β-arrestin complexes for sustained signaling.
  • To discover compounds with broad applicability across different GPCRs.

Main Methods:

  • Development and application of the survival pressure selection (SPS) method, a high-throughput platform for GPCR agonist discovery.
  • Identification of an allosteric ligand stabilizing a GPCR-G protein-β-arrestin megacomplex.
  • Testing the compound's pan-receptor activation across Family A GPCRs, including GPR119, β1AR, and β2AR.

Main Results:

  • An allosteric ligand, identified as atazanavir, was found to stabilize a GPCR-G protein-β-arrestin megacomplex.
  • This stabilization leads to sustained receptor signaling after receptor internalization.
  • Atazanavir demonstrated pan-receptor activation across multiple Family A GPCRs, including GPR119, β1AR, and β2AR.

Conclusions:

  • A novel mechanism of GPCR regulation involving the stabilization of a GPCR-G protein-β-arrestin megacomplex has been uncovered.
  • This mechanism allows for sustained GPCR signaling and offers broad applicability across various GPCRs.
  • The findings open new therapeutic avenues for developing drugs targeting GPCRs.