Disease Association and Druggability of WD40 Repeat Proteins
Abstract
WD40 repeat (WDR) domains are protein interaction scaffolds that represent one of the largest protein families in human, and a first WDR inhibitor-an allosteric antagonist of polycomb repressive complex 2-just entered the clinic. A systematic analysis of the CORUM database of protein complexes shows that WDR is the most represented domain in transcriptional regulation and one of the most prevalent in the ubiquitin proteasome system, two pathways of high relevance to drug discovery. Parsing the literature and the vulnerability of cancer cell lines to CRISPR knockout indicates that WDR proteins are targets of interest in oncology and other disease areas. A quantitative analysis of WDR structures reveals that druggable binding pockets can be found on multiple surfaces of these multifaceted protein interaction platforms. These data support the development of chemical probes to further interrogate WDR proteins as an emerging therapeutic target class.
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The central cavity of WDR domains can sometimes be positively or negatively charged, which reduces its ligandability.
“but this site can sometimes be positively or negatively charged, which reduces its ligandability 72 .”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [72]
The central cavity of WDR domains is generally deep and enclosed.
“The central cavity of WDR domains is generally deep and enclosed, two important properties for potent binding of chemical handles”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [72]
The central cavity of RBBP4 is highly basic compared to those of WDR5, EED, DCAF1, PAFAH1B1, ATG16L1 or ERCC8.
“the central cavity of DDB2 and RBBP4 are highly acidic and basic, respectively, compared to those of WDR5, EED, DCAF1, PAFAH1B1, ATG16L1 or ERCC8.”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [72]
The central cavity of DDB2 is highly acidic compared to those of WDR5, EED, DCAF1, PAFAH1B1, ATG16L1 or ERCC8.
“the central cavity of DDB2 and RBBP4 are highly acidic and basic, respectively, compared to those of WDR5, EED, DCAF1, PAFAH1B1, ATG16L1 or ERCC8.”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [72]
Cites
STRING v10: protein–protein interaction networks, integrated over the tree of life
Szklarczyk, D., Franceschini, A., Wyder, S., Forslund, K., Heller, D., Huerta-Cepas, J., Simonovic, M., Roth, A., Santos, A., Tsafou, K. P., et al. (2015) · Nucleic Acids Research · doi:10.1093/nar/gku1003 · Cited by 10,436 · see citing works
Interactive Tree Of Life (iTOL): an online tool for phylogenetic tree display and annotation
Letunić, I., & Peer Bork, B. (2006) · Bioinformatics · doi:10.1093/bioinformatics/btl529 · Cited by 3,326 · see citing works
Mutations in LRRK2 Cause Autosomal-Dominant Parkinsonism with Pleomorphic Pathology
Zimprich, A. A., Biskup, S., Leitner, P., Lichtner, P., Farrer, M. J., Lincoln, S., Kachergus, J. M., Hulihan, M., Uitti, R. J., Calne, D. B., et al. (2004) · Neuron · doi:10.1016/j.neuron.2004.11.005 · Cited by 3,024 · see citing works
Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1β production
Saitoh, T., Fujita, N., Jang, M. H., Uematsu, S., Yang, B., Satoh, T., Omori, H., Noda, T., Yamamoto, N., Komatsu, M., et al. (2008) · Nature · doi:10.1038/nature07383 · Cited by 2,009 · see citing works
Hampe, J., Franke, A., Rosenstiel, P. C., Till, A., Teuber, M., Huse, K., Albrecht, M., Gabriele Mayr, B., Vega, F. M. D. L., Briggs, J. C., et al. (2006) · Nature Genetics · doi:10.1038/ng1954 · Cited by 1,899 · see citing works
Identifying and Characterizing Binding Sites and Assessing Druggability
Halgren, T. A. (2009) · Journal of Chemical Information and Modeling · doi:10.1021/ci800324m · Cited by 1,771 · see citing works
Identification and characterization of essential genes in the human genome
Wang, T., Birsoy, K., Hughes, N. W., Krupczak, K. M., Post, Y., Wei, J. J., Lander, E. S., & Sabatini, D. M. (2015) · Science · doi:10.1126/science.aac7041 · Cited by 1,617 · see citing works
High-Resolution CRISPR Screens Reveal Fitness Genes and Genotype-Specific Cancer Liabilities.
Hart, T., Chandrashekhar, M., Aregger, M., Steinhart, Z., Brown, K. R., MacLeod, G., Mis, M., Zimmermann, M., Fradet-Turcotte, A., Sun, S., et al. (2015) · Cell · doi:10.1016/j.cell.2015.11.015 · Cited by 1,571 · see citing works
Healy, D. G., Falchi, M., O’Sullivan, S. S., Bonifati, V., Dürr, A., Bressman, S., Brice, A., Aasly, J. O., Zabetian, C. P., Goldwurm, S., et al. (2008) · The Lancet Neurology · doi:10.1016/s1474-4422(08)70117-0 · Cited by 1,523 · see citing works
Architecture of the human interactome defines protein communities and disease networks
Huttlin, E. L., Bruckner, R. J., Paulo, J. A., Cannon, J. R., Ting, L., Baltier, K., Colby, G., Gebreab, F., Gygi, M. P., Parzen, H., et al. (2017) · Nature · doi:10.1038/nature22366 · Cited by 1,437 · see citing works
CORUM: the comprehensive resource of mammalian protein complexes—2009
Ruepp, A., Wägele, B., Lechner, M., Brauner, B., Dunger-Kaltenbach, I., Fobo, G., Frishman, G., Montrone, C., & Mewes, H. (2009) · Nucleic Acids Research · doi:10.1093/nar/gkp914 · Cited by 1,320 · see citing works
PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene
Rahman, N., Seal, S., Thompson, D. J., Kelly, P. F., Renwick, A., Elliott, A., Reid, S., Spanova, K., Barfoot, R., Chagtai, T., et al. (2006) · Nature Genetics · doi:10.1038/ng1959 · Cited by 1,002 · see citing works
Structure and function of WD40 domain proteins
Xu, C., & Min, J. (2011) · Protein & Cell · doi:10.1007/s13238-011-1018-1 · Cited by 644 · see citing works
Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer
Reid, S., Schindler, D., Hanenberg, H., Barker, K., Hanks, S., Kalb, R., Neveling, K., Kelly, P., Seal, S., Freund, M., et al. (2007) · Nature Genetics · doi:10.1038/ng1947 · Cited by 642 · see citing works
Wang, T., Yu, H., Hughes, N. W., Liu, B., Kendirli, A., Klein, K., Chen, W. W., Lander, E. S., & Sabatini, D. M. (2017) · Cell · doi:10.1016/j.cell.2017.01.013 · Cited by 632 · see citing works
WD40 proteins propel cellular networks
Stirnimann, C. U., Petsalaki, E., Russell, R. B., & Müller, C. W. (2010) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2010.04.003 · Cited by 629 · see citing works
von Kleist, L., Stahlschmidt, W., Bulut, H., Gromova, K. V., Puchkov, D., Robertson, M. J., MacGregor, K. A., Tomilin, N. V., Pechstein, A., Chau, N., et al. (2011) · Cell · doi:10.1016/j.cell.2011.06.025 · Cited by 572 · see citing works
Structural Basis of UV DNA-Damage Recognition by the DDB1–DDB2 Complex
Scrima, A., Koníčková, R., Czyzewski, B. K., Kawasaki, Y., Jeffrey, P. D., Groisman, R., Nakatani, Y., Iwai, S., Pavletich, N. P., & Thomä, N. H. (2008) · Cell · doi:10.1016/j.cell.2008.10.045 · Cited by 441 · see citing works
Pocketome via Comprehensive Identification and Classification of Ligand Binding Envelopes
An, J., Totrov, M. M., & Abagyan, R. A. (2005) · Molecular & Cellular Proteomics · doi:10.1074/mcp.m400159-mcp200 · Cited by 408 · see citing works
A Crohn’s disease variant in Atg16l1 enhances its degradation by caspase 3
Murthy, A., Li, Y., Peng, I., Reichelt, M., Katakam, A. K., Noubade, R., Roose-Girma, M., DeVoss, J., Diehl, L., Graham, R. R., et al. (2014) · Nature · doi:10.1038/nature13044 · Cited by 381 · see citing works
Tumor suppression by the Fbw7 ubiquitin ligase: mechanisms and opportunities
Davis, R. J., Welcker, M., & Clurman, B. E. (2014) · Cancer Cell · doi:10.1016/j.ccell.2014.09.013 · Cited by 343 · see citing works
An allosteric PRC2 inhibitor targeting the H3K27me3 binding pocket of EED
Qi, W., Zhao, K., Gu, J., Huang, Y., Wang, Y., Zhang, H., Zhang, M., Zhang, J., Yu, Z., Li, L., et al. (2017) · Nature Chemical Biology · doi:10.1038/nchembio.2304 · Cited by 316 · see citing works
Self-citationPharmacological targeting of the Wdr5-MLL interaction in C/EBPα N-terminal leukemia
Grebien, F., Vedadi, M., Getlik, M., Giambruno, R., Grover, A., Avellino, R., Skucha, A., Vittori, S., Kuznetsova, E., Smil, D., et al. (2015) · Nature Chemical Biology · doi:10.1038/nchembio.1859 · Cited by 284 · see citing works
Self-citationSynergistic blockade of mitotic exit by two chemical inhibitors of the APC/C
Sackton, K. L., Dimova, N., Zeng, X., Tian, W., Zhang, M., Sackton, T. B., Meaders, J., Pfaff, K. L., Sigoillot, F., Yu, H., et al. (2014) · Nature · doi:10.1038/nature13660 · Cited by 257 · see citing works
Maréchal, A., Li, J.-M., Ji, X. Y., Wu, C.-S. P., Yazinski, S. A., Nguyen, H. D., Liu, S., Jiménez, A. E., Jin, J., & Zou, L. (2013) · Molecular Cell · doi:10.1016/j.molcel.2013.11.002 · Cited by 246 · see citing works
The EED protein–protein interaction inhibitor A-395 inactivates the PRC2 complex
He, Y., Selvaraju, S., Curtin, M. L., Jakob, C. G., Zhu, H., Comess, K. M., Shaw, B., The, J., Lima-Fernandes, E., Szewczyk, M. M., et al. (2017) · Nature Chemical Biology · doi:10.1038/nchembio.2306 · Cited by 224 · see citing works
Xu, C., Bian, C., Yang, W., Galka, M., Ouyang, H., Chen, C., Qiu, W., Liu, H., Jones, A. E., MacKenzie, F., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1008937107 · Cited by 221 · see citing works
Song, E. J., Werner, S. L., Neubauer, J., Stegmeier, F. P., Aspden, J. L., Rio, D. C., Harper, J. W., Elledge, S. J., Kirschner, M. W., & Rapé, M. (2010) · Genes & Development · doi:10.1101/gad.1925010 · Cited by 216 · see citing works
Erratum: Pharmacological targeting of the Wdr5-MLL interaction in C/EBPα N-terminal leukemia
Grebien, F., Vedadi, M., Getlik, M., Giambruno, R., Grover, A., Avellino, R., Skucha, A., Vittori, S., Kuznetsova, E., Smil, D. V., et al. (2015) · Nature Chemical Biology · doi:10.1038/nchembio1015-815b · Cited by 206 · see citing works
Self-citationSmall-molecule inhibition of MLL activity by disruption of its interaction with WDR5
Senisterra, G. A., Wu, H. Y., Allali‐Hassani, A., Wasney, G. A., Baršytė-Lovejoy, D., Dombrovski, L., Dong, A., Nguyen, K. T., Smil, D. V., Bolshan, Y., et al. (2012) · Biochemical Journal · doi:10.1042/bj20121280 · Cited by 165 · see citing works
Self-citationG-Protein β3 Subunit Gene ( GNB3 ) Variant in Causation of Essential Hypertension
Benjafield, A., Jeyasingam, C. L., Nyholt, D. R., et al. (1998) · Hypertension · doi:10.1161/01.hyp.32.6.1094 · Cited by 156 · see citing works
An allosteric inhibitor of substrate recognition by the SCFCdc4 ubiquitin ligase
Orlicky, S. M., Tang, X., Neduva, V., Elowe, N. H., Brown, E. D., Sicheri, F., & Tyers, M. (2010) · Nature Biotechnology · doi:10.1038/nbt.1646 · Cited by 150 · see citing works
ChromoHub: a data hub for navigators of chromatin-mediated signalling
Liu, L., Zhen, X. T., Denton, E., Marsden, B. D., & Schapira, M. (2012) · Bioinformatics · doi:10.1093/bioinformatics/bts340 · Cited by 96 · see citing works
Self-citationThe DDB1–DCAF1–Vpr–UNG2 crystal structure reveals how HIV-1 Vpr steers human UNG2 toward destruction
Wu, Y., Zhou, X., Barnes, C. O., DeLucia, M., Cohen, A. E., Gronenborn, A. M., Ahn, J., & Calero, G. A. (2016) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.3284 · Cited by 96 · see citing works
WDSPdb: a database for WD40-repeat proteins
Wang, Y., Hu, X.-J., Zou, X., Wu, X., Ye, Z., & Wu, Y. (2014) · Nucleic Acids Research · doi:10.1093/nar/gku1023 · Cited by 84 · see citing works
Hengstenberg, C. (2001) · Cardiovascular Research · doi:10.1016/s0008-6363(00)00292-3 · Cited by 84 · see citing works
Thomas, L. R., Foshage, A. M., Weissmiller, A. M., & Tansey, W. P. (2015) · Cancer Research · doi:10.1158/0008-5472.can-15-1216 · Cited by 69 · see citing works
Structural insights into Gemin5-guided selection of pre-snRNAs for snRNP assemblyPreprint
Xu, C., Ishikawa, H., Izumikawa, K., Li, L., He, H., Nobe, Y., Yamauchi, Y., Shahjee, H. M., Wu, X., Yu, Y., et al. (2016) · Genes & Development · doi:10.1101/gad.288340.116 · Cited by 69 · see citing works
HYPERTENSION, OBESITY AND GNB3 GENE VARIANTS
Danoviz, M. E., Pereira, A. C., Mill, J. G., & Krieger, J. E. (2006) · Clinical and Experimental Pharmacology and Physiology · doi:10.1111/j.1440-1681.2006.04353.x · Cited by 45 · see citing works
Couture, J., & Skiniotis, G. (2013) · Epigenetics · doi:10.4161/epi.24177 · Cited by 24 · see citing works
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Targeted protein degradation: expanding the toolbox
Schapira, M., Calabrese, M. F., Bullock, A. N., & Crews, C. M. (2019) · Nature Reviews Drug Discovery · doi:10.1038/s41573-019-0047-y · Cited by 960 · see citing works
Self-citationMacdonald, J. D., Chacón Simon, S., Han, C., Wang, F., Shaw, J. G., Howes, J. E., Sai, J., Yuh, J. P., Camper, D., Alicie, B. M., et al. (2019) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b01411 · Cited by 66 · see citing works
- Authors
- Song, R., Wang, Z.-D., & Schapira, M.
- Affiliations
- University of Toronto (CA)
- Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada
- Corresponding author
- Schapira, Matthieu
- Venue
- Journal of Proteome Research
- Publisher
- American Chemical Society (ACS)
- Published
- 2017-09-28
- Volume
- 16
- Issue
- 10
- Pages
- 3766-3773
- ISSN
- 1535-3893 (ISSN-L)
- 1535-3907
- OpenAlex
- W2758088381
- Cited by
- 45
- References
- 40
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 7 · 2023: 5 · 2022: 3 · 2021: 10 · 2020: 4 · 2019: 7 · 2018: 3
- FWCI
- 2.87
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Proteome Research (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bioinformatics and Genomic Networks
- Keywords
- WD40 repeat proteins, druggability, binding pocket, polycomb repressive complex 2, allosteric inhibitors, protein complexes, ubiquitin-proteasome system, transcriptional regulation, cancer cell lines, chemical probes, therapeutic target
- MeSH terms
- WD40 Repeats, Protein Domains, Animals, Antineoplastic Agents, Gene Expression Regulation, Humans, Neoplasms, Protein Binding, Protein Conformation, Ubiquitin, Proteasome Endopeptidase Complex, Gene Knockout Techniques, Drug Discovery, Polycomb Repressive Complex 2
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