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]
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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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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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