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WD40 repeat domain proteins: a novel target class?

Key Points

  • WD40 repeat (WDR) domains are β-propeller domains that act as protein interaction scaffolds in multiprotein complexes.

  • WDR domain-containing proteins comprise one of the largest protein families in humans and are involved in a diverse array of cellular networks, many of which are disease-associated.

  • The central cavity of the WDR domain is structurally dynamic and diverse. Potent, selective inhibitors target the central cavity of WD repeat-containing protein 5 (WDR5) and EED, two proteins involved in chromatin complexes. An EED inhibitor has entered clinical trials in oncology.

  • Targeting WDR domains that bind to other proteins that have so far proved undruggable, such as components of the ubiquitin–proteasome system, is a promising but underexplored strategy.

  • The cellular implications of pharmacologically targeting WDR domains that are involved in multiple protein complexes are still poorly understood.

Abstract

Antagonism of protein–protein interactions (PPIs) with small molecules is becoming more feasible as a therapeutic approach. Successful PPI inhibitors tend to target proteins containing deep peptide-binding grooves or pockets rather than the more common large, flat protein interaction surfaces. Here, we review one of the most abundant PPI domains in the human proteome, the WD40 repeat (WDR) domain, which has a central peptide-binding pocket and is a member of the β-propeller domain-containing protein family. Recently, two WDR domain-containing proteins, WDR5 and EED, as well as other β-propeller domains have been successfully targeted by potent, specific, cell-active, drug-like chemical probes. Could WDR domains be a novel target class for drug discovery? Although the research is at an early stage and therefore not clinically validated, cautious optimism is justified, as WDR domain-containing proteins are involved in multiple disease-associated pathways. The druggability and structural diversity of WDR domain binding pockets suggest that understanding how to target this prevalent domain class will open up areas of disease biology that have so far resisted drug discovery efforts.

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Figure 1: Protein interaction modes of WD40 repeat domain β-propellers.
Figure 2: WD40 repeat domain-containing proteins perform diverse cellular functions.
Figure 3: Epigenetic chemical probes against WD40 repeat domain-containing proteins.
Figure 4: Exemplar inhibitors of WD40 repeat domains and related β-propeller domains.
Figure 5: Structural dynamics of WD40 repeat domain binding pockets.

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Acknowledgements

The Structural Genomics Consortium (SGC) is a registered charity (number 1097737) that receives funds from AbbVie, Bayer Pharma, Boehringer Ingelheim, Canada Foundation for Innovation, Eshelman Institute for Innovation, Genome Canada through Ontario Genomics Institute (OGI-055), Innovative Medicines Initiative (EU/EFPIA) (ULTRA-DD grant no. 115766), Janssen, Merck & Co., Novartis Pharma AG, Ontario Ministry of Research, Innovation and Science (MRIS), Pfizer, São Paulo Research Foundation-FAPESP, Takeda and the Wellcome Trust. C.H.A. is supported by the Canadian Institute for Health Research (CIHR) (FRN-125792) and holds a Canada Research Chair in Structural Genomics. M.Ty. is supported by grants from the CIHR (MOP 126129), the Canadian Cancer Society Research Institute (703906), Genome Canada, Genome Quebec and National Institutes of Health (R01OD010929), and holds a Canada Research Chair in Systems and Synthetic Biology. The authors acknowledge Z.D. Wang for his contribution in generating the list of 361 WDR-containing proteins and C. Jakob for her careful review of the manuscript.

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Correspondence to Matthieu Schapira.

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M.To. is an employee of AbbVie and owns AbbVie stock. M.S., M.Ty. and C.H.A. declare no competing interests.

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Glossary

Thermal stabilization

A thermodynamic property used to screen chemical libraries, and which relies on the fact that the melting point of a protein often increases upon the binding of a small molecule.

Affinity selection–mass spectrometry

A screening technique whereby a protein is exposed to small molecules, receptor–ligand complexes are isolated and bound ligands are identified by mass spectrometry.

DNA-encoded libraries

Chemical libraries in which each small molecule is linked to a unique DNA fragment that serves as a barcode. These typically very large libraries can be interrogated by affinity selection.

High-throughput fragment screening

The screening of chemical libraries composed of chemical fragments (molecules smaller than 300 Da) typically at high concentration using direct binding rather than enzymatic assays.

Fluorescence polarization

Fluorescence-based binding assay that relies on the fact that free molecules rotate faster than large molecular complexes.

Apo state

The unbound state of a protein or other macromolecule, as opposed to the 'holo' state, when complexed to a ligand.

Bidentate ligands

Compounds with two chemical groups carrying distinct functions, for example each binding to a different protein interaction partner.

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Schapira, M., Tyers, M., Torrent, M. et al. WD40 repeat domain proteins: a novel target class?. Nat Rev Drug Discov 16, 773–786 (2017). https://doi.org/10.1038/nrd.2017.179

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