The DOI matches its Crossref record; 124 of the 124 references it cites were found in a registry or an index.
WD40 repeat domain proteins: a novel target class?
Open accessAbstract
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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“The crystal structure of the homologous DCAF1 in complex with VPR indicates that substrate recognition relies on the WDR domain, a doughnut-like proteininteraction module that, in the context of other proteins, has been successfully targeted by small-molecule ligands 67 (Fig. 4a):”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [67]
In the citing paper
“this site is shallow and looks unligandable in the apo-structure of EED”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [67]
In the citing paper
“conformational remodelling is necessary for ligand binding 67 .”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [67]
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Citations
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“WD repeat domains are known to interact with diverse binding partners, such as proteins, DNA, and RNA (52).”
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“…model for this interaction has a high ipTM score (0.83) and reveals that the WDR12 residues at the predicted interface fall within WD repeats 4-6, and the CSNK2B interface residues overlap the CK2α-interaction region, both of which are known to mediate protein-protein interactions 47,48 ( Fig.”
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“In addition to histones, transcription factors, RNA-binding proteins and members of chromatin-remodeling complexes (such as SWI/SNF) are also targets of chroma - tin-modifying enzymes [64, 65 ].”
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“WD40 repeats mediate diverse cellular processes, including signaling pathway regulation, chromatin remodeling, and the DNA damage response, by providing extensive protein–protein interaction surfaces [7].”
Female sterility: a new strategy for hybrid rice production
Silva, J. (2026) · PLANT PHYSIOLOGY · doi:10.1093/plphys/kiag160
“Through a bioinformatic analysis, Li and colleagues found that OsDPMS1 protein contained WD40 repeat domains, which are known to mediate protein interaction (Schapira et al. 2017).”
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The implication of class 3 PI3K in lysosomal membrane damage response in lysosomal storage disorders
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Class 3 PI3K ensures metabolic fitness through epigenetic control of nuclear gene transcription
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DeWildt, L. V., Hildenbrand, M. A., Manchester, C. D., Prawiradilaga, S. I., Ristoratore, F., & Coppola, U. (2026) · Frontiers in Ecology and Evolution · doi:10.3389/fevo.2026.1851122
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“WD repeat domains are known to interact with diverse binding partners, such as proteins, DNA, and RNA [ 65 ].”
The role of the WD40-repeat protein family in cancer
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The WD40 repeat protein OsDPMS1 controls pistil development and female fertility in rice
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LRS1 phosphorylated in response to blue light regulates stomatal opening
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“WDR proteins possess multiple blades forming a ß-pro-peller structure, and proteins containing seven blades are generally thought to exhibit higher structural stability (Mishra et al. 2012; Schapira et al. 2017).”
Świerczek, N., Ropka‐Molik, K., Piórkowska, K., Małopolska, M. M., Tyra, M., Szmatoła, T., Muszyński, S., & Quembo, C. J. (2026) · Veterinary Research Communications · doi:10.1007/s11259-026-11479-8
“…heterotrimeric G proteins (De Vries et al. 2000), cytoskeletal and microtubule organization (Baker et al. 2025), vesicular transport (Lupi et al. 2024), protein–protein interactions (Schapira et al. 2017), and control of protein stability via the ubiquitin–proteasome system (Kohroki et al. 2005).”
WDR12 Promotes Glucose Metabolism via PFKFB4 Upregulation in Gastric Cancer
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“Furthermore, WD40 repeat (WDR) domain-containing proteins are among the largest families in the human proteome that act as versatile scaffolds for protein – protein interactions (217) and maintain oncogenesis in various human cancers (218).”
BindingDB (2026) · UC San Diego · doi:10.7270/q2j1081p
BindingDB (2023) · UC San Diego · doi:10.7270/q2b85d61
BindingDB (2024) · UC San Diego · doi:10.7270/q2vq374f
Metadata
- Authors
- Schapira, M., Tyers, M., Torrent, M., & Arrowsmith, C. H.
- Affiliations
- University of Toronto (CA)
- Mount Sinai Hospital (CA)
- AbbVie (United States) (US)
- Corresponding author
- Schapira, Matthieu
- Venue
- Nature Reviews Drug Discovery
- Published
- 2017-10-13
- Volume
- 16
- Issue
- 11
- Pages
- 773-786
- ISSN
- 1474-1776 (ISSN-L)
- 1474-1784
- PMC
- PMC5975957
- OpenAlex
- W2761872853
- Cited by
- 335
- References
- 124
- Citations by year
- 2026: 33 · 2025: 40 · 2024: 54 · 2023: 50 · 2022: 43 · 2021: 50 · 2020: 28 · 2019: 22 · 2018: 15
- FWCI
- 1.66
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Reviews Drug Discovery (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Genome Canada
- Wellcome Trust
- Ontario Genomics Institute
- National Institutes of Health (R01OD010929)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Physical Sciences › Chemistry › Organic Chemistry › Chemical Synthesis and Analysis
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Computational Drug Discovery Methods
- Keywords
- WD40 repeat domain, WDR5, EED, protein-protein interaction inhibitors, small molecule drug discovery, beta-propeller proteins, peptide binding pocket, druggability, chromatin regulation
- MeSH terms
- WD40 Repeats, Animals, Humans, Molecular Targeted Therapy
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