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Conservation of Protein Domains Over Different Proteins02:26

Conservation of Protein Domains Over Different Proteins

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Protein domains are small structurally independent units that are part of a single amino acid chain.  Although these domains are often structurally independent, they may rely on synergistic effects to perform their functions as part of a larger protein. Protein domains may be conserved within the same organism, as well as across different organisms.
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Exploring Sequence Space to Identify Binding Sites for Regulatory RNA-Binding Proteins
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Identifying Small-Molecule Binding Sites for Epigenetic Proteins at Domain-Domain Interfaces.

David Bowkett1, Romain Talon1, Cynthia Tallant1

  • 1Structural Genomics Consortium (SGC) & Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, NDM Research Building, Roosevelt Drive, Oxford, OX3 7FZ, UK.

Chemmedchem
|March 27, 2018
PubMed
Summary

Targeting epigenetic reader domains for drug discovery is challenging. This study explores novel domain-domain interfaces as binding sites for small-molecule inhibitors, offering new therapeutic strategies.

Keywords:
X-ray fragment screeningbromodomainsepigeneticshistonestudor domains

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Area of Science:

  • Epigenetics and Drug Discovery
  • Structural Biology
  • Chemical Biology

Background:

  • Epigenetic modifications regulate gene expression and are key targets in drug discovery.
  • Inhibitor development for epigenetic reader domains faces challenges due to lack of well-defined binding sites.
  • Proteins involved in epigenetic regulation often possess multiple domains, suggesting potential for novel inhibition strategies.

Purpose of the Study:

  • To investigate the potential of targeting domain-domain interfaces for small-molecule inhibitor design in epigenetics.
  • To identify and validate novel binding pockets within multi-domain epigenetic proteins.

Main Methods:

  • Computational analysis of X-ray structures using the SiteMap algorithm to identify potential binding sites at domain-domain interfaces.
  • Experimental validation through X-ray crystallographic fragment screening.

Main Results:

  • SiteMap algorithm successfully identified potential binding sites at domain-domain interfaces of epigenetic proteins.
  • A specific inter-domain site in the tandem plant homeodomain-bromodomain of SP100C was computationally identified.
  • Experimental fragment screening validated the identified inter-domain site and discovered ligands.

Conclusions:

  • Targeting domain-domain interfaces represents a promising strategy for developing small-molecule inhibitors against epigenetic reader domains.
  • This approach overcomes limitations of targeting single domains and offers new avenues for epigenetic drug discovery.