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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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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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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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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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Agonists are drugs that interact with specific receptors in the body to produce a biological response. When an agonist binds to a receptor, it activates or enhances the receptor's function, leading to physiological effects. The interaction between agonist drugs and receptors is crucial for their therapeutic action in various medical treatments.
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Heterotrimeric G proteins are guanine nucleotide-binding proteins. As the name suggests, heterotrimeric G proteins are composed of three subunits: alpha, beta, and gamma. They remain GDP-bound or GTP-bound inside the cells and switch between inactive/active states. The Gα subunit possesses the nucleotide-binding pocket that binds guanine nucleotides and switches between GDP or GTP-bound states. In contrast, the Gꞵ and Gγ subunits are always bound together with high...
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Related Experiment Video

Updated: Sep 26, 2025

Detecting the Ligand-binding Domain Dimerization Activity of Estrogen Receptor Alpha Using the Mammalian Two-Hybrid Assay
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Allosteric interactions prime androgen receptor dimerization and activation.

Elizabeth V Wasmuth1, Arnaud Vanden Broeck2, Justin R LaClair3

  • 1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Laboratory of Protein and Nucleic Acid Chemistry, The Rockefeller University, New York, NY 10065, USA.

Molecular Cell
|April 21, 2022
PubMed
Summary
This summary is machine-generated.

Androgen receptor (AR) forms dimers to bind DNA cooperatively, a mechanism crucial for prostate development and cancer. This AR DNA-binding interface is targeted in disease and influenced by cofactors like ERG.

Keywords:
allosterycooperativitynuclear receptorprostate cancertranscription factors

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Area of Science:

  • Molecular biology
  • Structural biology
  • Genetics

Background:

  • The androgen receptor (AR) is vital for prostate development and male characteristics.
  • AR hyperactivation drives advanced prostate cancers, involving gene amplification and cofactor interactions.
  • Mechanisms of AR-DNA binding and cofactor cooperation remain unclear.

Purpose of the Study:

  • To elucidate the structural basis of androgen receptor (AR) DNA binding and cooperative interactions.
  • To investigate the role of AR domains and cofactors in DNA binding.
  • To understand how AR structural dynamics contribute to prostate development and cancer.

Main Methods:

  • Single-particle cryo-electron microscopy (cryo-EM) was used to determine AR-DNA complex structures.
  • Analysis of three distinct AR-DNA conformations.
  • Identification of allosteric surfaces and cofactor interactions.

Main Results:

  • AR forms a non-obligate dimer utilizing an ancestral interface for cooperative DNA binding.
  • Novel allosteric surfaces were identified, implicated in androgen insensitivity syndrome.
  • The cofactor ERG and DNA-binding motifs reinforce AR's cooperative DNA binding.
  • Evidence suggests the AR dimer interface is plastic, potentially favoring transactivation over DNA binding.

Conclusions:

  • AR's cooperative DNA binding is mediated by a flexible dimer interface, repurposed from ancestral receptors.
  • Dysregulation of this interface is linked to androgen insensitivity and prostate cancer progression.
  • Fine-tuning AR cooperative interactions impacts both normal development and disease states.