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Disease Association and Druggability of WD40 Repeat Proteins

Richard Song1, Zhong-Duo Wang1, Matthieu Schapira1,2

  • 1Structural Genomics Consortium, University of Toronto , Toronto, Ontario M5G 1L7, Canada.

Journal of Proteome Research
|September 29, 2017
PubMed

Insights

WD40 repeat (WDR) domains are crucial protein scaffolds involved in gene regulation and the ubiquitin system. These versatile protein interaction platforms present druggable targets for developing novel cancer therapies.

Area of Science:

  • Biochemistry and Molecular Biology
  • Structural Biology
  • Pharmacology

Background:

  • WD40 (WDR) repeat domains form large protein families and are key interaction scaffolds.
  • A WDR inhibitor targeting polycomb repressive complex 2 has recently entered clinical trials.
  • WDR domains are highly represented in transcriptional regulation and the ubiquitin proteasome system.

Purpose of the Study:

  • To systematically analyze the role and therapeutic potential of WD40 repeat proteins.
  • To investigate the druggability of WDR proteins based on structural analysis.
  • To support the development of chemical probes for WDR protein targets.

Main Methods:

  • Systematic analysis of the CORUM database of protein complexes.
  • Literature review and analysis of cancer cell line vulnerability to CRISPR knockout.
  • Quantitative analysis of WD40 repeat protein structures to identify binding pockets.

Main Results:

  • WD40 repeat domains are the most represented in transcriptional regulation and prevalent in the ubiquitin proteasome system.
  • WDR proteins are identified as targets of interest in oncology and other disease areas based on literature and CRISPR data.
  • Druggable binding pockets are present on multiple surfaces of WD40 repeat proteins.

Conclusions:

  • WD40 repeat proteins represent an emerging therapeutic target class.
  • The structural and functional data support the development of chemical probes to target WDR proteins.
  • Targeting WDR proteins holds promise for drug discovery in oncology and beyond.
Keywords:
CRISPR knockout screenWD40WDRcancerdisease associationdruggabilityhuman proteomeregulation of transcriptiontherapeutic targetubiquitin proteasome system

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