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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]
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“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]
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“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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“The WDR domain typically exhibits a seven-bladed β-propeller architecture with an overall doughnut shape, with which WDR domain-containing proteins mediate PPIs or protein-DNA interactions.(13,14) WDR domains are often essential subunits of protein complexes involved in a wide range of cellular processes, including G…”
BackgroundMethodInfluentialCRNKL1 Is a Highly Selective Regulator of Intron-Retaining HIV-1 and Cellular mRNAs
Xiao, H., Wyler, E., Milek, M., Grewe, B., Kirchner, P., Ekici, A. B., Silva, A. B. O. V., Jungnickl, D., Full, F., Thomas, M., et al. (2021) · mBio · doi:10.1128/mbio.02525-20 · Cited by 23
“WDR70 is not linked to splicing, however, 199 it contains a WD40 repeat domain which is shared by a number of splicing factors (46).”
BackgroundBiochemical Reduction of the Topology of the Diverse WDR76 Protein Interactome
Dayebgadoh, G., Sardiu, M. E., Florens, L. A., & Washburn, M. P. (2019) · Journal of Proteome Research · doi:10.1021/acs.jproteome.9b00373 · Cited by 22
Re‐examining the ‘Dissociation Model’ of G protein activation from the perspective of Gβγ signaling
Chung, Y. K., & Wong, Y. H. (2020) · FEBS Journal · doi:10.1111/febs.15605 · Cited by 22
The Rad9–Rad1–Hus1 DNA Repair Clamp is Found in Microsporidia
dos Santos, A. C. M., Julian, A. T., & Pombert, J. (2022) · Genome Biology and Evolution · doi:10.1093/gbe/evac053 · Cited by 21
“…folds, for example, the seven-bladed single β-propeller found in CSA, DDB2, and in so many more proteins (Henning et al. 1995; Fischer et al. 2011; Schapira et al. 2017), and the lack of sequence homology for many of the proteins featuring these repetitive folds prohibited us from assigning them…”
Ahmad, S., Xu, J. B., Feng, J. A., Hutchinson, A., Zeng, H., Ghiabi, P., Dong, A., Centrella, P. A., Clark, M., Guié, M.-A., et al. (2023) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.3c01471 · Cited by 22
Small Molecules Targeting the Specific Domains of Histone-Mark Readers in Cancer Therapy
Zhu, H., Wei, T., Cai, Y., & Jin, J. (2020) · Molecules · doi:10.3390/molecules25030578 · Cited by 23
Cell Cycle Regulation by Heat Shock Transcription Factors
Tokunaga, Y., Otsuyama, K., & Hayashida, N. (2022) · Cells · doi:10.3390/cells11020203 · Cited by 21
NSUN5 Facilitates Hepatocellular Carcinoma Progression by Increasing SMAD3 Expression
Han, H., Zhang, C., Shi, W., Wang, J., Zhao, W., Du, Y., Zhao, Z., Wang, Y., Lin, M., Qin, L., et al. (2024) · Advanced Science · doi:10.1002/advs.202404083 · Cited by 21
WD40 protein Wuho controls germline homeostasis via TRIM-NHL tumor suppressor Mei-p26 in Drosophila
Rastegari, E., Kajal, K., Tan, B. S., Huang, F., Chen, R., Hsieh, T.-S., & Hsu, H. (2020) · Development · doi:10.1242/dev.182063 · Cited by 17
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“Phosphorylated CDPs bind to the WD40 domain of FBXW7, and the target protein is recognized and degraded by the ubiquitination system [5, 6].”
BackgroundQin, Y., Yan, G., Qiao, Y., Wang, D., & Tang, C. (2023) · BMC Genomics · doi:10.1186/s12864-023-09892-3 · Cited by 23
“Of note, WDR43 is an essential subunit of multiprotein complexes and is involved in a series of signaling pathways including ubiquitin-proteasome pathway, epigenetic regulation, DNA damage repair, and immune-related pathways [32].”
BackgroundZhang, L., Hao, P., Chen, X., Lv, S., Gao, W., Li, C., Li, Z., & Zhang, W. (2024) · mBio · doi:10.1128/mbio.03071-23 · Cited by 21
CACHE Challenge #1: Docking with GNINA Is All You Need
Dunn, I. C., Pirhadi, S., Wang, Y., Ravindran, S., Concepcion, C., & Koes, D. R. (2024) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.4c01429 · Cited by 20
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Accogli, A., Shakya, S., Yang, T., Insinna, C., Kim, S. Y., Bell, D. R., Butov, K. R., Severino, M., Niceta, M., Scala, M., et al. (2024) · Nature Communications · doi:10.1038/s41467-023-44611-2 · Cited by 19
“WDR44isamemberofthelargeWD40-repeat(WDR)family,which is characterized by a fi ve to eight bladed β -propeller structure arranged radially around a central channel, giving a donut-like appearance 16,17 .”
Li, Z., Feng, M., Zhang, J., Wang, X., Xu, E., Wang, C., Lin, F., Yang, Z., Yu, H., Guan, W., et al. (2021) · Cancer Cell International · doi:10.1186/s12935-021-02109-1 · Cited by 19
Identification of WDR12 as a novel oncogene involved in hepatocellular carcinoma propagation
Yin, Y., Zhou, L., Zhan, R., Zhang, Q., & Li, M. (2018) · Cancer Management and Research · doi:10.2147/cmar.s176268 · Cited by 19
“15 Thus, our findings may be helpful in designing new therapeutic strategies for patients with HCC.”
Small molecule and peptide inhibitors of βTrCP and the βTrCP–NRF2 protein–protein interaction
Jaffry, U., & Wells, G. (2023) · Biochemical Society Transactions · doi:10.1042/bst20220352 · Cited by 18
He, X., Huang, N., Qiu, Y., Zhang, J., Liu, Y., Yin, X., & Lu, S. (2021) · Molecules · doi:10.3390/molecules26040962 · Cited by 18
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Cai, L., Liu, B., Cao, Y., Sun, T., & Li, Y. (2023) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2023.1276612 · Cited by 17
“Its main characteristic, the highly conserved WD40 repeat (WDR) domain, is the most functionally diverse domain discovered, and over a thousand WDR domains have been annotated currently (Schapira et al., 2017; Ma et al., 2019).”
BackgroundShen, L., Fang, J. J., Liu, L., Yang, F., Jenkins, J. L., Kutchukian, P. S., & Wang, H. (2024) · Journal of Cheminformatics · doi:10.1186/s13321-024-00829-w · Cited by 17
“The WD40 repeat (WDR) domain-containing proteins comprise one of the most abundant PPI domains in the human proteome, playing crucial roles in various cellular processes, including numerous disease-associated mechanisms [22, 23].”
BackgroundChi, Z., Zhang, B., Sun, R., Wang, Y., Zhang, L., & Xu, G. (2022) · International Journal of Medical Sciences · doi:10.7150/ijms.74535 · Cited by 16
“The WD repeat protein family members regulate various cellular events and are considered as potential targets for disease treatment [16].”
BackgroundGenome-Wide Identification, Evolution, and Expression Analysis of the WD40 Subfamily in Oryza Genus
Ke, S., Jiang, Y., Zhou, M., & Li, Y. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms242115776 · Cited by 16
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“The WDR domain typically comprises seven - bladed β-propellers and involves various protein–protein interactions as scaffold proteins ( 20 ).”
Novel Machado-Joseph disease-modifying genes and pathways identified by whole-exome sequencing
Raposo, M., Bettencourt, C., Melo, A. R. V., Ferreira, A. F., Alonso, I. D. C. M. P., Silva, P., Vasconcelos, J., Kay, T. T., Pereira, M. L. S., Costa, M. D., et al. (2021) · Neurobiology of Disease · doi:10.1016/j.nbd.2021.105578 · Cited by 16
Structural basis for an unprecedented enzymatic alkylation in cylindrocyclophane biosynthesis
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An Update on the Interplay between LRRK2, Rab GTPases and Parkinson’s Disease
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RELATe enables genome-scale engineering in fungal genomics
Li, Z., & Kim, K. S. (2020) · Science Advances · doi:10.1126/sciadv.abb8783 · Cited by 14
G protein β5-ATM complexes drive acetaminophen-induced hepatotoxicity
Pramanick, A., Chakraborti, S., Mahata, T., Basak, M., Das, K., Verma, S. K., Sengar, A. S., Singh, P. K., Kumar, P., Bhattacharya, B., et al. (2021) · Redox Biology · doi:10.1016/j.redox.2021.101965 · Cited by 15
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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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