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Related Concept Videos

Cooperative Allosteric Transitions01:58

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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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Transcriptional regulators bind to specific cis-regulatory sequences in the DNA to regulate gene transcription. These cis-regulatory sequences are very short, usually less than ten nucleotide pairs in length. The short length means that there is a high probability of the exact same sequence randomly occurring throughout the genome.  Since regulators can also bind to groups of similar sequences, this further increases the chances of random binding. Transcriptional regulators form...
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The receptor occupancy theory connects a drug's response to the number of occupied receptors. With higher drug concentrations, more receptors are occupied, leading to increased responses. The formation of drug-receptor complexes involves association and dissociation rates, which reach equilibrium when the forward and backward reactions are equal. The equilibrium association constant (Ka) and its inverse, the equilibrium dissociation constant (Kd), indicate drug affinity. Higher Ka and lower...
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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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Gene transcription is regulated by the synergistic action of several proteins that form a complex at a gene regulatory site. This is observed in eukaryotes, where the regulation of gene expression is a complex process. Regulatory proteins in eukaryotes can broadly be classified into two types – regulators that bind directly to specific DNA sequences and co-regulators that associate with regulatory proteins but cannot directly bind to the DNA. These co-regulators are further divided into...
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Cooperativity as quantification and optimization paradigm for nuclear receptor modulators.

Pim J de Vink1, Auke A Koops1, Giulia D'Arrigo1,2

  • 1Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems, Eindhoven University of Technology P. O. Box 513 5600MB Eindhoven The Netherlands l.brunsveld@tue.nl.

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This summary is machine-generated.

Nuclear Receptors (NRs) are modulated by ligands acting as molecular glues. A new thermodynamic model quantifies this cooperativity, aiding the discovery of novel NR modulators.

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Nuclear Receptors (NRs) are crucial drug targets.
  • NR-ligand interactions involve modulating Protein-Protein Interactions (PPIs) with coregulators.
  • Existing modulation paradigms focus on simple ligand/receptor binding.

Purpose of the Study:

  • To introduce a cooperativity mechanism for small molecule modulation of NR PPIs.
  • To describe NR-ligands as allosteric molecular glues.
  • To provide a framework for understanding NR-ligand-coregulator ternary complex formation.

Main Methods:

  • Development of a thermodynamic model based on three-body binding events.
  • Dissection and quantification of reciprocal binding effects (NR-coregulator and NR-ligand).
  • Utilizing the Peroxisome Proliferator Activated Receptor γ (PPARγ) as a model system.

Main Results:

  • Quantification of NR-coregulator binding (KID) and NR-ligand binding (KIID).
  • Introduction of the cooperativity factor (α) for ternary complex formation.
  • Demonstration of a framework for analyzing ligand-induced allosteric modulation of NR PPIs.

Conclusions:

  • NR-ligands can function as allosteric molecular glues.
  • The thermodynamic framework offers a novel approach to structure-activity relationships for NR modulators.
  • This approach can guide the discovery and optimization of NR-targeted therapeutics.