WD40 repeat domain proteins: a novel target class?

Schapira, Matthieu; Tyers, Mike; Torrent, Maricel; Arrowsmith, Cheryl H.

doi:10.1038/nrd.2017.179

Cited by 346Protein Degradation and InhibitorsChemical Synthesis and AnalysisComputational Drug Discovery Methods

WD40 repeat domain proteins: a novel target class?

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Schapira, Matthieu, Tyers, Mike, Torrent, Maricel, Arrowsmith, Cheryl H.·2017·Nature Reviews Drug Discovery

DOI 10.1038/nrd.2017.179PMC PMC5975957

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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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The crystal structure of the homologous DCAF1 in complex with VPR indicates that substrate recognition relies on the WDR domain, a doughnut-like protein-interaction module that, in the context of other proteins, has been successfully targeted by small-molecule ligands.
“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 apo-structure of EED, the central cavity is shallow and looks unligandable.
“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]
Conformational remodelling of EED is necessary for ligand binding.
“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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Structural basis for distinctive recognition of fibrinogen γC peptide by the platelet integrin αIIbβ3
Springer, T. A., Zhu, J., & Xiao, T. S. (2008) · The Journal of Cell Biology · doi:10.1083/jcb.200801146 · Cited by 235 · see citing works
Affinity selection-mass spectrometry screening techniques for small molecule drug discovery
Annis, D. A., Nickbarg, E., Yang, X., Ziebell, M. R., & Whitehurst, C. E. (2007) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2007.07.011 · Cited by 226 · 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
Self-citation
Increased LIS1 expression affects human and mouse brain development
Bi, W., Sapir, T., Shchelochkov, O. A., Zhang, F., Withers, M. A., Hunter, J. V., Levy, T., Shinder, V., Peiffer, D. A., Gunderson, K. L., et al. (2009) · Nature Genetics · doi:10.1038/ng.302 · Cited by 223 · see citing works
CDC20, a potential cancer therapeutic target, is negatively regulated by p53
Kidokoro, T., Tanikawa, C., Furukawa, Y., Katagiri, T., Nakamura, Y., & Matsuda, K. (2007) · Oncogene · doi:10.1038/sj.onc.1210799 · Cited by 208 · 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-citation
LRRK2 Parkinson disease mutations enhance its microtubule association
Kett, L. R., Boassa, D., Ho, C. C., Rideout, H. J., Hu, J., Terada, M., Ellisman, M. H., & Dauer, W. T. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr526 · Cited by 196 · see citing works
RACK1 Controls IRES-Mediated Translation of Viruses
Majzoub, K., Hafirassou, M. L., Meignin, C., Goto, A., Marzi, S., Fedorova, A. A., Verdier, Y., Vinh, J., Hoffmann, J. A., Martin, F., et al. (2014) · Cell · doi:10.1016/j.cell.2014.10.041 · Cited by 195 · see citing works
The many blades of the β-propeller proteins: conserved but versatile
Chen, C. K.-M., Chan, N., & Wang, A. H. ‐. (2011) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2011.07.004 · Cited by 185 · see citing works
A TGFβ-PRMT5-MEP50 axis regulates cancer cell invasion through histone H3 and H4 arginine methylation coupled transcriptional activation and repression
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Novel BET protein proteolysis-targeting chimera exerts superior lethal activity than bromodomain inhibitor (BETi) against post-myeloproliferative neoplasm secondary (s) AML cells
Saenz, D. T., Fiskus, W. C., Qian, Y., Manshouri, T., Rajapakshe, K., Raina, K., Coleman, K. G., Crew, A. P. A., Shen, A., Mill, C. P., et al. (2017) · Leukemia · doi:10.1038/leu.2016.393 · Cited by 184 · see citing works
Recruitment of Phosphorylated Chromatin Assembly Factor 1 to Chromatin after UV Irradiation of Human Cells
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Small-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-citation
Identification of EZH2 and EZH1 Small Molecule Inhibitors with Selective Impact on Diffuse Large B Cell Lymphoma Cell Growth
Garapaty, S., Nasveschuk, C. G., Gagnon, A., Chan, E. Y., Sandy, P., Busby, J., Balasubramanian, S., Campbell, R., Zhao, F., Bergeron, L., et al. (2013) · Chemistry & Biology · doi:10.1016/j.chembiol.2013.09.013 · Cited by 154 · 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
Self-citation
Development of secondary mutations in wild-type and mutant EZH2 alleles cooperates to confer resistance to EZH2 inhibitors
Gibaja, V, Shen, F., Harari, J., Korn, J., Ruddy, D., Saenz-Vash, V, Zhai, H., Rejtar, T., Paris, C. G., Yu, Z., et al. (2016) · Oncogene · doi:10.1038/onc.2015.114 · Cited by 149 · see citing works
Structural basis of lentiviral subversion of a cellular protein degradation pathway
Schwefel, D., Groom, H. C. T., Boucherit, V., Christodoulou, E., Walker, P. A., Stoye, J. P., Bishop, K. N., & Taylor, I. A. (2013) · Nature · doi:10.1038/nature12815 · Cited by 127 · see citing works
Structural and Biochemical Insights into MLL1 Core Complex Assembly
Avdic, V., Zhang, P., Lanouette, S., Groulx, A. F., Tremblay, V., Brunzelle, J. S., & Couture, J. (2011) · Structure · doi:10.1016/j.str.2010.09.022 · Cited by 117 · see citing works
The WD40 Domain Is Required for LRRK2 Neurotoxicity
Jorgensen, N. D., Peng, Y., Ho, C. C., Rideout, H. J., Petrey, D. S., Liu, P., & Dauer, W. T. (2009) · PLoS ONE · doi:10.1371/journal.pone.0008463 · Cited by 111 · see citing works
JAK2 rearrangements, including the novel SEC31A-JAK2 fusion, are recurrent in classical Hodgkin lymphoma
Roosbroeck, K. V., Cox, L., Tousseyn, T., Lahortiga, I., Gielen, O., Cauwelier, B., Paepe, P. D., Verhoef, G. E. G., Marynen, P., Vandenberghe, P., et al. (2011) · Blood · doi:10.1182/blood-2010-06-291310 · Cited by 111 · see citing works
A CDC20-APC/SOX2 Signaling Axis Regulates Human Glioblastoma Stem-like Cells
Mao, D. D., Gujar, A. D., Mahlokozera, T., Chen, I., Pan, Y., Luo, J. R., Brost, T. M., Thompson, E. A., Turski, A., Leuthardt, E. C., et al. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.05.027 · Cited by 110 · see citing works
ALK-positive large B-cell lymphomas with cryptic SEC31A-ALK and NPM1-ALK fusions
Roosbroeck, K. V., Cools, J., Dierickx, D., Thomas, J., Vandenberghe, P., Stul, M. S., Delabie, J., Wolf‐Peeters, C. D., Marynen, P., & Włodarska, I. (2010) · Haematologica · doi:10.3324/haematol.2009.014761 · Cited by 104 · see citing works
Discovery of First-in-Class, Potent, and Orally Bioavailable Embryonic Ectoderm Development (EED) Inhibitor with Robust Anticancer Efficacy
Huang, Y. R., Zhang, J., Yu, Z., Zhang, H., Wang, Y., Lingel, A., Qi, W., Gu, J., Zhao, K., Shultz, M. D., et al. (2017) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b01576 · Cited by 104 · see citing works
The 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
Structure-Based Optimization of a Small Molecule Antagonist of the Interaction Between WD Repeat-Containing Protein 5 (WDR5) and Mixed-Lineage Leukemia 1 (MLL1)
Getlik, M., Smil, D. V., Zepeda‐Velázquez, C., Bolshan, Y., Poda, G. I., Wu, H. Y., Dong, A., Kuznetsova, E., Marcellus, R. C., Senisterra, G. A., et al. (2016) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5b01630 · Cited by 94 · see citing works
Self-citation
A chemical probe toolbox for dissecting the cancer epigenome
Shortt, J., Ott, C. J., Johnstone, R. W., & Bradner, J. E. (2017) · Nature reviews. Cancer · doi:10.1038/nrc.2016.148 · Cited by 94 · see citing works
Novel LRRK2 GTP-binding inhibitors reduced degeneration in Parkinson's disease cell and mouse models
Li, T., Yang, D., Zhong, S., Thomas, J. M., Xue, F., Liu, J., Kong, L., Voulalas, P. J., Hassan, H. E., Park, J.-S., et al. (2014) · Human Molecular Genetics · doi:10.1093/hmg/ddu341 · Cited by 85 · 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
Acquisition of a single EZH2 D1 domain mutation confers acquired resistance to EZH2-targeted inhibitors
Baker, T. E., Nerle, S., Pritchard, J. R., Zhao, B., Rivera, V. M., Garner, A. P., & Gonzalvez, F. (2015) · Oncotarget · doi:10.18632/oncotarget.5066 · Cited by 78 · see citing works
Initial testing (stage 1) of the PARP inhibitor BMN 673 by the pediatric preclinical testing program: PALB2 mutation predicts exceptional in vivo response to BMN 673
Smith, M. A., Hampton, O. A., Reynolds, C. P., Kang, M. H., Maris, J. M., Gorlick, R. G., Kolb, E. A., Lock, R. B., Carol, H., Keir, S. T., et al. (2014) · Pediatric Blood & Cancer · doi:10.1002/pbc.25201 · Cited by 74 · see citing works
Synthesis, Optimization, and Evaluation of Novel Small Molecules as Antagonists of WDR5-MLL Interaction
Bolshan, Y., Getlik, M., Kuznetsova, E., Wasney, G. A., Hajian, T., Poda, G. I., Nguyen, K. T., Wu, H. Y., Dombrovski, L., Dong, A., et al. (2013) · ACS Medicinal Chemistry Letters · doi:10.1021/ml300467n · Cited by 74 · see citing works
Self-citation
Intragenic deletions and duplications of the LIS1 and DCX genes: a major disease-causing mechanism in lissencephaly and subcortical band heterotopia
Haverfield, E. V., Whited, A. J., Petras, K. S., Dobyns, W. B., & Das, S. (2008) · European Journal of Human Genetics · doi:10.1038/ejhg.2008.213 · Cited by 73 · see citing works
Retinoblastoma Binding Protein 4 Modulates Temozolomide Sensitivity in Glioblastoma by Regulating DNA Repair Proteins
Kitange, G. J., Mladek, A. C., Schroeder, M. A., Pokorny, J. C., Carlson, B. L., Zhang, Y., Nair, A., Lee, J., Yan, H., Decker, P. A., et al. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.02.045 · Cited by 73 · see citing works
Gene expression profiling in glioblastoma and immunohistochemical evaluation of IGFBP-2 and CDC20
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MLL1 Inhibition Reprograms Epiblast Stem Cells to Naive Pluripotency
Zhang, H., Gayen, S., Xiong, J., Zhou, B. O., Shanmugam, A. K., Sun, Y., Karataş, H., Liu, L., Rao, R. C., Wang, S., et al. (2016) · Cell stem cell · doi:10.1016/j.stem.2016.02.004 · Cited by 68 · see citing works
The GNB3 C825T polymorphism as a pharmacogenetic marker in the treatment of hypertension, obesity, and depression
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Co-repressor complexes and remodelling chromatin for repression
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VprBP Has Intrinsic Kinase Activity Targeting Histone H2A and Represses Gene Transcription
Kim, K., Kim, J., Kim, J., Choi, J., Lee, Y. S., Neamati, N., Song, J. S., Heo, K., & An, W. (2013) · Molecular Cell · doi:10.1016/j.molcel.2013.09.017 · Cited by 61 · see citing works
A Method for WD40 Repeat Detection and Secondary Structure Prediction
Wang, Y., Jiang, F., Zhuo, Z., Wu, X., & Wu, Y. (2013) · PLoS ONE · doi:10.1371/journal.pone.0065705 · Cited by 57 · see citing works
CDC20 maintains tumor initiating cells
Xie, Q., Wu, Q., Mack, S. C., Yang, K., Kim, L., Hubert, C. G., Flavahan, W. A., Chu, C., Bao, S., & Rich, J. N. (2015) · Oncotarget · doi:10.18632/oncotarget.3676 · Cited by 55 · see citing works
Preclinical target validation using patient-derived cells
Edwards, A. M., Arrowsmith, C. H., Bountra, C., Bunnage, M. E., Feldmann, M., Knight, J. C., Patel, D. D., Prinos, P., Taylor, M. D., Sundström, M., et al. (2015) · Nature Reviews Drug Discovery · doi:10.1038/nrd4565 · Cited by 54 · see citing works
Self-citation
Discovery and Molecular Basis of a Diverse Set of Polycomb Repressive Complex 2 Inhibitors Recognition by EED
Li, L., Zhang, H., Zhang, M., Zhao, M., Feng, L., Luo, X., Gao, Z., Huang, Y. R., Ardayfio, O., Zhang, J.-H., et al. (2017) · PLoS ONE · doi:10.1371/journal.pone.0169855 · Cited by 53 · see citing works
The scaffold protein RACK1 mediates the RANKL-dependent activation of p38 MAPK in osteoclast precursors
Lin, J., Lee, D., Choi, Y., & Lee, S. Y. (2015) · Science Signaling · doi:10.1126/scisignal.2005867 · Cited by 49 · see citing works
Structural basis for streptogramin B resistance in Staphylococcus aureus by virginiamycin B lyase
Korczynska, M., Mukhtar, T. A., Wright, G. D., & Berghuis, A. M. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0701809104 · Cited by 46 · see citing works
Unclosed β-Propellers Display Stable Structures: Implications for Substrate Access to the Active Site of Prolyl Oligopeptidase
Juhász, T., Szeltner, Z., Fülöp, V., & Polgár, L. (2004) · Journal of Molecular Biology · doi:10.1016/j.jmb.2004.12.014 · Cited by 42 · see citing works
Cytogenetically complex SEC31A-ALK fusions are recurrent in ALK-positive large B-cell lymphomas
Bedwell, C., Rowe, D. W., Moulton, D., Jones, G., Bown, N. P., & Bacon, C. M. (2010) · Haematologica · doi:10.3324/haematol.2010.031484 · Cited by 39 · see citing works
Structural basis for a class of nanomolar influenza A neuraminidase inhibitors
Kerry, P. S., Mohan, S., Russell, R. J. M., Bance, N., Niikura, M., & Pinto, B. M. (2013) · Scientific Reports · doi:10.1038/srep02871 · Cited by 37 · see citing works
An allosteric conduit facilitates dynamic multisite substrate recognition by the SCFCdc4 ubiquitin ligase
Csizmók, V., Orlicky, S. M., Cheng, J., Song, J., Bah, A., Delgoshaie, N., Lin, H., Mittag, T., Sicheri, F., Chan, H. S., et al. (2017) · Nature Communications · doi:10.1038/ncomms13943 · Cited by 36 · see citing works
Self-citation
Mouse model implicates GNB3 duplication in a childhood obesity syndrome
Goldlust, I. S., Hermetz, K. E., Catalano, L. M., Barfield, R., Cozad, R., Wynn, G. M., Ozdemir, A. C., Conneely, K. N., Mulle, J. G., Dharamrup, S., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1305999110 · Cited by 32 · see citing works
SAR of amino pyrrolidines as potent and novel protein-protein interaction inhibitors of the PRC2 complex through EED binding
Curtin, M. L., Pliushchev, M. A., Li, H., Torrent, M., Dietrich, J. D., Jakob, C. G., Zhu, H., Zhao, H., Wang, Y., Ji, Z., et al. (2017) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2017.02.030 · Cited by 30 · see citing works
Self-citation
Integrating population variation and protein structural analysis to improve clinical interpretation of missense variation: application to the WD40 domain
Laskowski, R., Tyagi, N., Johnson, D. S., Joss, S., Kinning, E., Mcwilliam, C., Splitt, M., Thornton, J., Firth, H., & Wright, C. (2016) · Human Molecular Genetics · doi:10.1093/hmg/ddv625 · Cited by 25 · see citing works

Flagged first, then by citations

Sorted by citations

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-citation
Epigenetic tools (The Writers, The Readers and The Erasers) and their implications in cancer therapy
Biswas, S., & Rao, C. M. (2018) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2018.08.021 · Cited by 402 · see citing works
Imidazoles as Potential Anticancer Agents: An Update on Recent Studies
Sharma, P., LaRosa, C., Antwi, J., Govindarajan, R., & Werbovetz, K. A. (2021) · Molecules · doi:10.3390/molecules26144213 · Cited by 220 · see citing works
Targeting G protein-coupled receptor signalling by blocking G proteins
Campbell, A. P., & Smrcka, A. V. (2018) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2018.135 · Cited by 189 · see citing works
A selective WDR5 degrader inhibits acute myeloid leukemia in patient-derived mouse models
Yu, X., Li, D., Kottur, J., Shen, Y., Kim, H. S., Park, K., Tsai, Y., Gong, W., Wang, J., Suzuki, K., et al. (2021) · Science Translational Medicine · doi:10.1126/scitranslmed.abj1578 · Cited by 154 · see citing works
Rhodopsin, light-sensor of vision
Hofmann, K. P., & Lamb, T. D. (2022) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2022.101116 · Cited by 126 · see citing works
Genome Features and Biochemical Characteristics of a Robust, Fast Growing and Naturally Transformable Cyanobacterium Synechococcus elongatus PCC 11801 Isolated from India
Jaiswal, D., Sengupta, A., Sohoni, S. V., Sengupta, S., Phadnavis, A. G., Pakrasi, H. B., & Wangikar, P. P. (2018) · Scientific Reports · doi:10.1038/s41598-018-34872-z · Cited by 120 · see citing works
FBW7 Mediates Senescence and Pulmonary Fibrosis through Telomere Uncapping
Wang, L., Chen, R., Li, G., Wang, Z., Liu, J., Liang, Y., & Liu, J. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2020.10.004 · Cited by 109 · see citing works
Tracking the PROTAC degradation pathway in living cells highlights the importance of ternary complex measurement for PROTAC optimization
Schwalm, M. P., Krämer, A., Dölle, A., Weckesser, J., Yu, X., Jin, J. J., Saxena, K., & Knapp, S. (2023) · Cell chemical biology · doi:10.1016/j.chembiol.2023.06.002 · Cited by 98 · see citing works
DCAF1-based PROTACs with activity against clinically validated targets overcoming intrinsic- and acquired-degrader resistance
Schröder, M., Renatus, M., Liang, X., Meili, F., Zoller, T., Ferrand, S., Gauter, F., Li, X., Sigoillot, F. D., Gleim, S., et al. (2024) · Nature Communications · doi:10.1038/s41467-023-44237-4 · Cited by 108 · see citing works
“If this is strictly required, could the authors comment on any implication in drug development and potential PK liabilities - Half-life of DCAF1 (is it known from literature? have the team measured this?)”
PROTAC degraders as chemical probes for studying target biology and target validation
Němec, V., Schwalm, M. P., Müller, S., & Knapp, S. (2022) · Chemical Society Reviews · doi:10.1039/d2cs00478j · Cited by 98 · see citing works
Target 2035 – update on the quest for a probe for every protein
Müller, S., Ackloo, S. Z., Chawaf, A. A., Al‐Lazikani, B., Antolín, A. A., Baell, J. B., Beck, H., Beedie, S., Betz, U. A. K., Bezerra, G. A., et al. (2021) · RSC Medicinal Chemistry · doi:10.1039/d1md00228g · Cited by 85 · see citing works
Self-citation
New insights into the mechanism of dynein motor regulation by lissencephaly-1
Markus, S. M., Marzo, M. G., & McKenney, R. J. (2020) · eLife · doi:10.7554/elife.59737 · Cited by 74 · see citing works
“WD-40 domains often function as multi-protein interaction platforms, suggesting this surface could act as a scaffold for recruitment of various LIS1-interacting regulators and targets (Schapira et al., 2017).”
Background
Novel epigenetic therapeutic strategies and targets in cancer
Babar, Q., Saeed, A., Tabish, T. A., Pricl, S., Townley, H. E., & Thorat, N. D. (2022) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2022.166552 · Cited by 76 · see citing works
Computer-Aided Drug Design in Epigenetics
Lu, W., Zhang, R., Jiang, H., Zhang, H., & Luo, C. (2018) · Frontiers in Chemistry · doi:10.3389/fchem.2018.00057 · Cited by 72 · see citing works
“…the readers associated with lysine methylation include PHD zinc ﬁnger domains, WD40, Tudor, double/tandem Tudor, MBT, Ankyrin Repeats, zf-CW, PWWP, and chromodomains (Kim et al., 2006; Collins et al., 2008; Musselman and Kutateladze, 2009; He et al., 2010; Rona et al., 2016; Schapira et al., 2017).”
Background
Discovery and Optimization of Salicylic Acid-Derived Sulfonamide Inhibitors of the WD Repeat-Containing Protein 5–MYC Protein–Protein Interaction
Macdonald, 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
Targeting DCAF5 suppresses SMARCB1-mutant cancer by stabilizing SWI/SNF
Radko-Juettner, S., Yue, H., Myers, J., Carter, R. D., Robertson, A. N., Mittal, P., Zhu, Z., Hansen, B. S., Donovan, K. A., Hunkeler, M., et al. (2024) · Nature · doi:10.1038/s41586-024-07250-1 · Cited by 65 · see citing works
Targeting WD Repeat-Containing Protein 5 (WDR5): A Medicinal Chemistry Perspective
Chen, X., Xu, J., Wang, X., Long, G., You, Q., & Guo, X. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c00037 · Cited by 63 · see citing works
HBx Protein Contributes to Liver Carcinogenesis by H3K4me3 Modification Through Stabilizing WD Repeat Domain 5 Protein
Gao, W., Jia, Z., Tian, Y., Yang, P., Sun, H., Wang, C., Ding, Y., Zhang, M., Zhang, Y., Yang, D., et al. (2019) · Hepatology · doi:10.1002/hep.30947 · Cited by 60 · see citing works
“These data suggest that the HBx-WDR5 interaction may serve as an effective drug target for HBV-induced tumors, in line with the feasibility of antagonizing protein–protein interactions with small molecules as a therapeutic approach.(34) Our results indeed show that treatment with WDR5-0103—a small molecule that binds…”
Result
ATG16L1 functions in cell homeostasis beyond autophagy
Hamaoui, D., & Subtil, A. (2021) · FEBS Journal · doi:10.1111/febs.15833 · Cited by 58 · see citing works
Functional Roles of Bromodomain Proteins in Cancer
Boyson, S. P., Gao, C., Quinn, K. M., Boyd, J. R., Paculová, H., Frietze, S. E., & Glass, K. C. (2021) · Cancers · doi:10.3390/cancers13143606 · Cited by 58 · see citing works
Targeting non-bromodomain chromatin readers
Arrowsmith, C. H., & Schapira, M. (2019) · Nature Structural & Molecular Biology · doi:10.1038/s41594-019-0290-2 · Cited by 58 · see citing works
Self-citation
RETRACTED ARTICLE: Restoring the Taxol biosynthetic machinery of Aspergillus terreus by Podocarpus gracilior Pilger microbiome, with retrieving the ribosome biogenesis proteins of WD40 superfamily
El‐Sayed, A. S. A., Mohamed, N. Z., Safan, S., Yassin, M. A., Shaaban, L., Shindia, A. A., Ali, G. S., & Sitohy, M. Z. (2019) · Scientific Reports · doi:10.1038/s41598-019-47816-y · Cited by 57 · see citing works
Retracted
Structural and Functional Insights into GID/CTLH E3 Ligase Complexes
Maitland, M. E. R., Lajoie, G., Shaw, G. S., & Schild‐Poulter, C. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23115863 · Cited by 49 · see citing works
The c-MYC-WDR43 signalling axis promotes chemoresistance and tumour growth in colorectal cancer by inhibiting p53 activity
Di, Y., Jing, X., Hu, K., Wen, X., Ye, L., Zhang, X., Qin, J., Ye, J., Lin, R., Wang, Z., et al. (2022) · Drug Resistance Updates · doi:10.1016/j.drup.2022.100909 · Cited by 53 · see citing works
Epigenetic small molecule modulators of histone and DNA methylation
Hauser, A., Robaa, D., & Jung, M. (2018) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2018.03.003 · Cited by 50 · see citing works
Discovery of Potent and Selective WDR5 Proteolysis Targeting Chimeras as Potential Therapeutics for Pancreatic Cancer
Yu, X., Li, D., Kottur, J., Kim, H. S., Herring, L. E., Yu, Y., Xie, L., Hu, X., Chen, X., Cai, L., et al. (2023) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.3c01521 · Cited by 43 · see citing works
The WD40 domain of FBXW7 is a poly(ADP-ribose)-binding domain that mediates the early DNA damage response
Zhang, Q., Mady, A. S. A., Ma, Y., Ryan, C., Lawrence, T. S., Nikolovska‐Coleska, Z., Sun, Y., & Morgan, M. A. (2019) · Nucleic Acids Research · doi:10.1093/nar/gkz058 · Cited by 41 · see citing works
“phospho-Ser/Thr) as well as damaged DNA (13).”
De Novo Missense Variants in WDR37 Cause a Severe Multisystemic Syndrome
Reis, L. M., Sorokina, E. A., Thompson, S., Muheisen, S., Velinov, M. T., Zamora, C. A., Aylsworth, A. S., & Semina, E. V. (2019) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2019.06.015 · Cited by 40 · see citing works
The WD40 domain-containing protein Ehd5 positively regulates flowering in rice ( Oryza sativa )
Zhang, X., Feng, Q., Miao, J., Zhu, J., Zhou, C., Fan, D., Lu, Y., Tian, Q., Wang, Y., Zhan, Q., et al. (2023) · The Plant Cell · doi:10.1093/plcell/koad223 · Cited by 39 · see citing works
“The structure of ELP2 and Elongator complex in yeast and human have been revealed, which revealed that ELP2 is the core component of this complex and indispensable (Dong et al. 2015; Dauden et al. 2017; Schapira et al. 2017).”
Background
AtRTP5 negatively regulates plant resistance to Phytophthora pathogens by modulating the biosynthesis of endogenous jasmonic acid and salicylic acid
Li, W., Zhao, D., Dong, J., Kong, X., Zhang, Q., Li, T., Meng, Y., & Shan, W. (2019) · Molecular Plant Pathology · doi:10.1111/mpp.12883 · Cited by 37 · see citing works
“WDR domain-containing proteins participate in signal transduction, transcriptional regulation, plant organ development and innate immunity, providing platforms for protein– protein and protein–DNA interactions or constituting multiprotein complexes (Perfus-Barbeoch et al., 2004; Schapira et al., 2017).”
BackgroundInfluential
Loss-of-Function Mutations in TRAF7 and KLF4 Cooperatively Activate RAS-Like GTPase Signaling and Promote Meningioma Development
Najm, P., Zhao, P., Steklov, M. Y., Sewduth, R. N., Baietti, M. F., Pandolfi, S., Criem, N., Lechat, B., Maia, T. M., Haver, D. V., et al. (2021) · Cancer Research · doi:10.1158/0008-5472.can-20-3669 · Cited by 37 · see citing works
“TheWD40 domain was reported to have a scaffolding structure known to be involved in the interaction with small GTPases (33, 34).”
Background
Computational design of symmetrical eight-bladed β-propeller proteins
Noguchi, H., Addy, C., Simoncini, D., Wouters, S. M. L., Mylemans, B., Meervelt, L. V., Schiex, T., Zhang, K. Y. J., Tame, J. R. H., & Voet, A. R. D. (2018) · IUCrJ · doi:10.1107/s205225251801480x · Cited by 36 · see citing works
Targeting protein methylation: from chemical tools to precision medicines
Dilworth, D., & Baršytė-Lovejoy, D. (2019) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03147-9 · Cited by 35 · see citing works
“WD-40 repeats are one of the most abundant scaffolding domains in the proteome and play a significant role in facilitating the connectivity of cellular networks [87].”
Background
Orchestrating serine/threonine phosphorylation and elucidating downstream effects by short linear motifs
Kliche, J., & Ivarsson, Y. (2022) · Biochemical Journal · doi:10.1042/bcj20200714 · Cited by 34 · see citing works
Structure-based view of the druggable genome
Wang, J., Yazdani, S., Han, A., & Schapira, M. (2020) · Drug Discovery Today · doi:10.1016/j.drudis.2020.02.006 · Cited by 34 · see citing works
Self-citation
Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7
Castilla‐Vallmanya, L., Selmer, K. K., Dimartino, C., Rabionet, R., Blanco‐Sánchez, B., Yang, S., Reijnders, M. R. F., van Essen, A. J., Oufadem, M., Vigeland, M. D., et al. (2020) · Genetics in Medicine · doi:10.1038/s41436-020-0792-7 · Cited by 34 · see citing works
RNA-interference screen for p53 regulators unveils a role of WDR75 in ribosome biogenesis
Moudrý, P., Chromá, K., Bursać, S., Volarević, S., & Bártek, J. (2021) · Cell Death and Differentiation · doi:10.1038/s41418-021-00882-0 · Cited by 34 · see citing works
Discovery of a Novel DCAF1 Ligand Using a Drug–Target Interaction Prediction Model: Generalizing Machine Learning to New Drug Targets
Kimani, S., Owen, J., Green, S. R., Li, F., Li, Y., Dong, A., Brown, P. J., Ackloo, S. Z., Kuter, D., Yang, C. L.-H., et al. (2023) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.3c00082 · Cited by 33 · see citing works
“4 None of the identified substrates are shared between the CRL4 DCAF1 and EDVP DCAF1 E3 ligase complexes, highlighting DCAF1 as a unique protein that can service two distinct E3 ubiquitin ligases, 10 which makes it an attractive target for the development of targeted protein degraders including…”
BackgroundSelf-citation
Implications of frequent hitter E3 ligases in targeted protein degradation screens
Zhang, X., Simon, G. M., & Cravatt, B. F. (2025) · Nature Chemical Biology · doi:10.1038/s41589-024-01821-z · Cited by 33 · see citing works
“For example, some DCAFs contain a WD40 repeat domain 22 , whereas others do not.”
Bistable Photoswitch Allows in Vivo Control of Hematopoiesis
Albert, L., Nagpal, J. K., Steinchen, W., Zhang, L., Werel, L., Djoković, N., Ružić, D., Hoffarth, M., Xu, J., Kaspareit, J., et al. (2021) · ACS Central Science · doi:10.1021/acscentsci.1c00434 · Cited by 33 · see citing works
ZWC complex-mediated SPT5 phosphorylation suppresses divergent antisense RNA transcription at active gene promoters
Park, K., Zhong, J., Jang, J. S., Kim, J., Kim, H., Lee, J., & Kim, J. (2022) · Nucleic Acids Research · doi:10.1093/nar/gkac193 · Cited by 33 · see citing works
CACHE Challenge #1: Targeting the WDR Domain of LRRK2, A Parkinson’s Disease Associated Protein
Li, F., Ackloo, S. Z., Arrowsmith, C. H., Ban, F., Barden, C., Beck, H., Beránek, J., Berenger, F., Bolotokova, A., Bret, G., et al. (2024) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.4c01267 · Cited by 34 · see citing works
Self-citation
Structure Based Design of Bicyclic Peptide Inhibitors of RbAp48
Hart, P. ‘., Hommen, P., Noisier, A. F. M., Krzyzanowski, A., Schüler, D., Porfetye, A. T., Akbarzadeh, M., Vetter, I. R., Adihou, H., & Waldmann, H. (2020) · Angewandte Chemie International Edition · doi:10.1002/anie.202009749 · Cited by 32 · see citing works
Association of host protein VARICOSE with HCPro within a multiprotein complex is crucial for RNA silencing suppression, translation, encapsidation and systemic spread of potato virus A infection
De, S., Pollari, M., Varjosalo, M. T., & Mäkinen, K. M. (2020) · PLoS Pathogens · doi:10.1371/journal.ppat.1008956 · Cited by 32 · see citing works
“These domains provide a platform for the reversible assembly of multiprotein complexes [24,25].”
Background
Aberrant Activity of Histone–Lysine N-Methyltransferase 2 (KMT2) Complexes in Oncogenesis
Poreba, E., Leśniewicz, K., & Durzynska, J. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21249340 · Cited by 22 · see citing works
“Since WDR5 is only required for the catalytic activity of KMT2A complexes and RBBP5 is an obligatory component regulating all other KMT2 complexes, it could be assumed that RBBP5 antagonists may exert broader inhibitory actions compared to agents targeting WDR5 [146,245,285,286].”
Background
Emerging functions of cytoskeletal proteins in immune diseases
Tur-Gracia, S., & Martı́nez-Quiles, N. (2021) · Journal of Cell Science · doi:10.1242/jcs.253534 · Cited by 31 · see citing works
Disentangling the recognition complexity of a protein hub using a nanopore
Mayse, L. A., Imran, A., Larimi, M. G., Cosgrove, M. S., Wolfe, A. J., & Movileanu, L. (2022) · Nature Communications · doi:10.1038/s41467-022-28465-8 · Cited by 31 · see citing works
Genetic background and PfKelch13 affect artemisinin susceptibility of PfCoronin mutants in Plasmodium falciparum
Sharma, A. I., Shin, S. H., Bopp, S. E. R., Volkman, S. K., Hartl, D. L., & Wirth, D. F. (2020) · PLoS Genetics · doi:10.1371/journal.pgen.1009266 · Cited by 30 · see citing works
Calcium flux control by Pacs1‐Wdr37 promotes lymphocyte quiescence and lymphoproliferative diseases
Nair‐Gill, E., Bonora, M., Zhong, X. Y., Liu, A., Miranda, A., Stewart, N. M., Ludwig, S. M., Russell, J. L., Gallagher, T. F., Pinton, P., et al. (2021) · The EMBO Journal · doi:10.15252/embj.2020104888 · Cited by 30 · see citing works
Expression profiling of WD40 family genes including DDB1- and CUL4- associated factor (DCAF) genes in mice and human suggests important regulatory roles in testicular development and spermatogenesis
Mistry, B. V., Alanazi, M., Fitwi, H., Al‐Harazi, O., Rajab, M., Altorbag, A., Almohanna, F., Çolak, D., & Assiri, A. M. (2020) · BMC Genomics · doi:10.1186/s12864-020-07016-9 · Cited by 28 · see citing works
Recognition of the CCT5 di‐Glu degron by CRL4DCAF12 is dependent on TRiC assembly
Pla‐Prats, C., Cavadini, S., Kempf, G., & Thomä, N. H. (2023) · The EMBO Journal · doi:10.15252/embj.2022112253 · Cited by 25 · see citing works
DCAF7 Acts as A Scaffold to Recruit USP10 for G3BP1 Deubiquitylation and Facilitates Chemoresistance and Metastasis in Nasopharyngeal Carcinoma
Li, Q., Fang, X., Li, Y., Lin, J., Huang, C., He, S., Huang, S., Li, J., Gong, S., Liu, N., et al. (2024) · Advanced Science · doi:10.1002/advs.202403262 · Cited by 26 · see citing works
Nuclear farnesoid X receptor protects against bone loss by driving osteoblast differentiation through stabilizing RUNX2
Dong, Q. Z., Fu, H., Li, W., Ji, X., Yin, Y., Zhang, Y., Zhu, Y., Li, G., Jia, H., Zhang, H., et al. (2025) · Bone Research · doi:10.1038/s41413-024-00394-w · Cited by 29 · see citing works
Translation of Mycobacterium Survival Strategy to Develop a Lipo‐peptide based Fusion Inhibitor**
Sardar, A., Lahiri, A., Kamble, M., Mallick, A. I., & Tarafdar, P. K. (2020) · Angewandte Chemie International Edition · doi:10.1002/anie.202013848 · Cited by 27 · see citing works
CoRe: a robustly benchmarked R package for identifying core-fitness genes in genome-wide pooled CRISPR-Cas9 screens
Vinceti, A., Karakoç, E., Pacini, C., Perron, U., Lucia, R. R. D., Garnett, M. J., & Iorio, F. (2021) · BMC Genomics · doi:10.1186/s12864-021-08129-5 · Cited by 27 · see citing works
“…genes, proteasome, RNA polymerase [36]), as well as other plausible families, such as proteins involved in the initiation phase of eukaryotic translation [38], chaperonins [39], nucleoporins [40, 41] and less immediate hits, such as AAA-ATPase [42, 43] and WD repeat domain families [44, 45].”
Background
Chemical biology and pharmacology of histone lysine methylation inhibitors
Barghout, S. H., Machado, R. A. C., & Baršytė-Lovejoy, D. (2022) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2022.194840 · Cited by 27 · see citing works
Chromatin-Associated Protein Complexes Link DNA Base J and Transcription Termination in Leishmania
Jensen, B. C., Phan, I. Q., McDonald, J. R., Sur, A., Gillespie, M. A. K., Ranish, J. A., Parsons, M., & Myler, P. J. (2021) · mSphere · doi:10.1128/msphere.01204-20 · Cited by 26 · see citing works
“For example, JBP3 contains a domain with structural similarity to the N-terminal TFIIS protein 344 interaction domain found in mammalian PNUTS and WD proteins can act as a scaffold in other 345 complexes (39, 40).”
Background
In silico modeling human VPS13 proteins associated with donor and target membranes suggests lipid transfer mechanisms
Dall’Armellina, F., Stagi, M., & Swan, L. E. (2022) · Proteins Structure Function and Bioinformatics · doi:10.1002/prot.26446 · Cited by 26 · see citing works
“A C-terminal domain of VPS13 proteins was previously described as a tryptophan-aspartic acid (WD40) or a β-propeller-like domain depending on differently predicted structural folds.(8,59,73) The VPS13 Adaptor”
Background
Targeting Epigenetic protein–protein Interactions With small-molecule Inhibitors
Linhares, B. M., Grembecka, J. E., & Cierpicki, T. (2020) · Future Medicinal Chemistry · doi:10.4155/fmc-2020-0082 · Cited by 25 · see citing works
Genome-wide identification and analysis of NOD-like receptors and their potential roles in response to Edwardsiella tarda infection in black rockfish (Sebastes schlegelii)
Cao, M., Yan, X., Li, Q., Fu, Q., Yang, N., Song, L., & Li, C. (2021) · Aquaculture · doi:10.1016/j.aquaculture.2021.736803 · Cited by 25 · see citing works
A Target Class Ligandability Evaluation of WD40 Repeat-Containing Proteins
(2024) · doi:10.1021/acs.jmedchem.4c02010 · Cited by 24 · see citing works
Self-citation
Chemical inhibitors targeting histone methylation readers
Huang, X., Chen, Y., Xiao, Q., Shang, X., & Liu, Y. (2024) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2024.108614 · Cited by 24 · see citing works
WD40-Repeat Proteins in Ciliopathies and Congenital Disorders of Endocrine System
Kim, Y.-J., & Kim, S. (2020) · Endocrinology and Metabolism · doi:10.3803/enm.2020.302 · Cited by 23 · see citing works
“Currently, more than 360 additional domains are reported in WDR proteins [6].”
Background
Biochemical perspectives on targeting KMT2 methyltransferases in cancer
Zhai, X., & Brownell, J. E. (2021) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2021.05.002 · Cited by 24 · see citing works
RACK1 facilitates breast cancer progression by competitively inhibiting the binding of β-catenin to PSMD2 and enhancing the stability of β-catenin
Tian, R., Tian, J., Zuo, X., Ren, S., Zhang, H., Liu, H., Wang, Z., Cui, Y., Niu, R., & Zhang, F. (2023) · Cell Death and Disease · doi:10.1038/s41419-023-06191-3 · Cited by 24 · see citing works
“The receptor for activated C kinase 1 (RACK1) is a member of the tryptophan-aspartate repeat (WDR) protein family [1].”
Genome-scale exon perturbation screens uncover exons critical for cell fitness
Xiao, M., Damodaran, A. P., Kumari, B., Dickson, E., Xing, K., On, T. A., Parab, N., King, H. E., Perez, A. R., Guiblet, W. M., et al. (2024) · Molecular Cell · doi:10.1016/j.molcel.2024.05.024 · Cited by 23 · see citing works
Clinical significance and biological function of WD repeat domain 54 as an oncogene in colorectal cancer
Yuan, Y., Qi, G., Shen, H., Guo, A., Cao, F., Zhu, Y., Xiao, C., Chang, W., & Zheng, S. (2018) · International Journal of Cancer · doi:10.1002/ijc.31736 · Cited by 23 · see citing works
“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…”
BackgroundMethodInfluential
CRNKL1 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 · see citing works
“WDR70 is not linked to splicing, however, 199 it contains a WD40 repeat domain which is shared by a number of splicing factors (46).”
Background
Biochemical 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 21 · see citing works
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 · see citing works
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 · see citing works
“…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…”
Discovery of a First-in-Class Small-Molecule Ligand for WDR91 Using DNA-Encoded Chemical Library Selection Followed by Machine Learning
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 · see citing works
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 22 · see citing works
Cell Cycle Regulation by Heat Shock Transcription Factors
Tokunaga, Y., Otsuyama, K., & Hayashida, N. (2022) · Cells · doi:10.3390/cells11020203 · Cited by 21 · see citing works
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 · see citing works
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 · see citing works
FBXW7 loss of function promotes esophageal squamous cell carcinoma progression via elevating MAP4 and ERK phosphorylation
Pan, Y., Liu, J., Gao, Y., Guo, Y., Wang, C., Liang, Z., Wu, M., Qian, Y., Li, Y., Shen, J., et al. (2023) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-023-02630-3 · Cited by 21 · see citing works
“Phosphorylated CDPs bind to the WD40 domain of FBXW7, and the target protein is recognized and degraded by the ubiquitination system [5, 6].”
Background
Identification of hub genes based on integrated analysis of single-cell and microarray transcriptome in patients with pulmonary arterial hypertension
Qin, Y., Yan, G., Qiao, Y., Wang, D., & Tang, C. (2023) · BMC Genomics · doi:10.1186/s12864-023-09892-3 · Cited by 20 · see citing works
“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].”
Background
CRL4B E3 ligase recruited by PRPF19 inhibits SARS-CoV-2 infection by targeting ORF6 for ubiquitin-dependent degradation
Zhang, 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 · see citing works
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 · see citing works
Tomosyn regulates the small RhoA GTPase to control the dendritic stability of neurons and the surface expression of AMPA receptors
Shen, W., Kilander, M. B. C., Bridi, M. S., Frei, J. A., Niescier, R. F., Huang, S., & Lin, Y. (2020) · Journal of Neuroscience Research · doi:10.1002/jnr.24608 · Cited by 20 · see citing works
Variants in the WDR44 WD40-repeat domain cause a spectrum of ciliopathy by impairing ciliogenesis initiation
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 · see citing works
“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 .”
WD40 repeat 43 mediates cell survival, proliferation, migration and invasion via vimentin in colorectal cancer
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 · see citing works
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 · see citing works
“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 · see citing works
Conformational Selection Mechanism Provides Structural Insights into the Optimization of APC-Asef Inhibitors
He, X., Huang, N., Qiu, Y., Zhang, J., Liu, Y., Yin, X., & Lu, S. (2021) · Molecules · doi:10.3390/molecules26040962 · Cited by 18 · see citing works
WDR87 interacts with CFAP47 protein in the middle piece of spermatozoa flagella to participate in sperm tail assembly
Liao, H., Guo, Z.-Y., Huang, L., Liu, G., Lü, J., Zhang, Y., & Xing, X. (2022) · Molecular Human Reproduction · doi:10.1093/molehr/gaac042 · Cited by 16 · see citing works
Unveiling the molecular structure and role of RBBP4/7: implications for epigenetic regulation and cancer research
Cai, L., Liu, B., Cao, Y., Sun, T., & Li, Y. (2023) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2023.1276612 · Cited by 17 · see citing works
“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).”
Background
Pocket Crafter: a 3D generative modeling based workflow for the rapid generation of hit molecules in drug discovery
Shen, 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 · see citing works
“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].”
Background
USP44 accelerates the growth of T-cell acute lymphoblastic leukemia through interacting with WDR5 and repressing its ubiquitination
Chi, 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 · see citing works
“The WD repeat protein family members regulate various cellular events and are considered as potential targets for disease treatment [16].”
Background
Genome-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 · see citing works
WDR20 prevents hepatocellular carcinoma senescence by orchestrating the simultaneous USP12/46-mediated deubiquitination of c-Myc
Li, J., Qi, X., Lai, M., Zhou, J., Yuan, M., You, J., Liu, Q., Pan, J., Zhao, L., Ying, M., et al. (2024) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2407904121 · Cited by 16 · see citing works
“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 · see citing works
Structural basis for an unprecedented enzymatic alkylation in cylindrocyclophane biosynthesis
Braffman, N. R., Ruskoski, T. B., Davis, K. M., Glasser, N. R., Johnson, C., Okafor, C. D., Boal, A. K., & Balskus, E. P. (2022) · eLife · doi:10.7554/elife.75761 · Cited by 16 · see citing works
WD repeat protein 54-mediator of ErbB2-driven cell motility 1 axis promotes bladder cancer tumorigenesis and metastasis and impairs chemosensitivity
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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
ORCID: Schapira, Matthieu
Tyers, Mike
Arrowsmith, Cheryl H.
Venue: Nature Reviews Drug Discovery
Publisher: Springer Science and Business Media LLC
Published: 2017-10-13
Volume: 16
Issue: 11
Pages: 773-786
ISSN: 1474-1776 (ISSN-L)
1474-1784
DOI: 10.1038/nrd.2017.179
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
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
Physical Sciences › Computer Science › Computational Theory and Mathematics › 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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WD40 repeat domain proteins: a novel target class?

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