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Ligand Binding Sites02:40

Ligand Binding Sites

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Proteins are dynamic macromolecules that carry out a wide variety of essential processes; however, the activities of most proteins depend on their interactions with other molecules or ions, known as ligands.
Protein-ligand interactions are quite specific; even though numerous potential ligands surround a cellular protein at any given time, only a particular ligand can bind to that protein. Moreover, a ligand binds only to a dedicated area on the surface of the protein, known as the...
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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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Many proteins’ biological role depends on their interactions with their ligands, small molecules that bind to specific locations on the protein known as ligand-binding sites. Ligand-binding sites are often conserved among homologous proteins as these sites are critical for protein function.
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A Target Class Ligandability Evaluation of WD40 Repeat-Containing Proteins.

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  • 1Structural Genomics Consortium, University of Toronto, 101 College St., Toronto, ON M5G 1L7, Canada.

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Researchers developed scalable methods to find small molecule ligands for the WD40 repeat (WDR) protein family. This approach identified new drug-like ligands, showing WDR proteins are druggable and opening avenues for new therapeutics.

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Area of Science:

  • Drug discovery and development
  • Structural biology
  • Chemical biology

Background:

  • Target class-focused drug discovery is effective, but many protein families, like WD40 repeat (WDR) proteins, lack known small molecule ligands.
  • The WDR protein family is highly relevant in disease but remains underexplored for therapeutic targeting.

Purpose of the Study:

  • To develop a systematic and scalable approach for discovering and characterizing small molecule ligands for the WDR protein family.
  • To evaluate the broader ligandability of WDR proteins and establish a template for family-wide assessment.

Main Methods:

  • Developed comprehensive protocols for protein production, crystallography, and various biophysical, biochemical, and cellular assays.
  • Employed DNA-encoded chemical library selection combined with machine learning (DEL-ML) for hit identification.
  • Screened virtual libraries to predict potential ligands.

Main Results:

  • Successfully identified first-in-class, drug-like small molecule ligands for 7 out of 16 screened WDR domains.
  • Demonstrated the significant ligandability of the WDR protein family.
  • Generated a comprehensive resource of biochemical and chemical tools, knowledge, and protocols for WDR proteins.

Conclusions:

  • The developed systematic approach provides a scalable template for evaluating protein family-wide ligandability.
  • The findings highlight the therapeutic potential of targeting the WDR protein family, previously considered underexplored.
  • This study provides valuable tools and knowledge to accelerate the discovery of potential therapeutics for WDR-related diseases.