The DOI matches its Crossref record; 25 of the 25 references it cites were found in a registry or an index.
Protacs: Chimeric molecules that target proteins to the Skp1–Cullin–F box complex for ubiquitination and degradation
Open accessAbstract
The intracellular levels of many proteins are regulated by ubiquitin-dependent proteolysis. One of the best-characterized enzymes that catalyzes the attachment of ubiquitin to proteins is a ubiquitin ligase complex, Skp1-Cullin-F box complex containing Hrt1 (SCF). We sought to artificially target a protein to the SCF complex for ubiquitination and degradation. To this end, we tested methionine aminopeptidase-2 (MetAP-2), which covalently binds the angiogenesis inhibitor ovalicin. A chimeric compound, protein-targeting chimeric molecule 1 (Protac-1), was synthesized to recruit MetAP-2 to SCF. One domain of Protac-1 contains the IκBα phosphopeptide that is recognized by the F-box protein β-TRCP, whereas the other domain is composed of ovalicin. We show that MetAP-2 can be tethered to SCF β -TRCP , ubiquitinated, and degraded in a Protac-1-dependent manner. In the future, this approach may be useful for conditional inactivation of proteins, and for targeting disease-causing proteins for destruction.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“Proteolysis-targeting chimeras (PROTACs) are bifunctional molecules designed to simultaneously engage a protein of interest and the cell’s ubiquitination machinery, facilitating the ubiquitination of the target protein [73,74].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [74]
In the citing paper
“Bivalent degraders, such as proteolysis-targeting chimeras (PROtAcs) operate through the principle of induced proximity (Sakamoto et al. 2001;Deshaies 2015).”
From From serendipity to strategy: molecular glue degraders in cancer therapeutics (2025) · cites this paper as Sakamoto et al. 2001
In the citing paper
“the concept of targeted protein degradation was first introduced by crews, Deshaies and colleagues in 2001 (Sakamoto et al. 2001).”
From From serendipity to strategy: molecular glue degraders in cancer therapeutics (2025) · cites this paper as Sakamoto et al. 2001
In the citing paper
“Within this complex, the target protein is tagged with ubiquitin, facilitating its recognition and subsequent degradation by the proteasome.480,481”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [481]
In the citing paper
“As a heterobifunctional molecule, PROTAC simultaneously targets the protein of interest and the E3 ubiquitin ligase, forming a ternary complex.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [481]
In the citing paper
“At the core of PROTAC’s mechanism of action lies the degradation of target proteins via the ubiquitin-proteasome system (UPS).”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [481]
In the citing paper
“TPD uses small molecules (degraders) to hijack the cellular degradation machinery by recruiting E3 ubiquitin ligases to proteins of interest (POI), which would not otherwise be recognized as substrates (Sakamoto et al., 2001)”
From Mapping the Degradable Kinome Provides a Resource for Expedited Degrader Development (2020) · cites this paper as Sakamoto et al., 2001
In the citing paper
“If these two groups are connected via a carefully-chosen chemical linker, the resulting compound can induce formation of a ternary complex that includes the target protein, the PROTAC, and the E3 ligase. The resulting proximity between target protein and E3 ligase can then lead to ubiquitination of the target protein, and ultimately its degradation 1.”
From Rationalizing PROTAC-Mediated Ternary Complex Formation Using Rosetta (2021) · cites this paper as [1]
In the citing paper
“Protac-1 acted as a tether between METAP2 and β-TRCP, enabling the ligase to ubiquitylate METAP2 in extracts from unfertilized Xenopus laevis eggs.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [9]
In the citing paper
“In vitro proof of concept for the first fully synthetic PROTAC, dubbed Protac-1, was reported in 2001 (ref.9).”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [9]
In the citing paper
“a concept originally proposed in the landmark PROTAC paper by Sakamoto et al.9 20 years ago.”
From PROTAC targeted protein degraders: the past is prologue (2022) · cites this paper as [9]
In the citing paper
“The first PROTAC described consisted of an ovalicin headgroup that bound methionine-aminopeptidase 2 (MetAP-2) linked to an IκBα derived peptide headgroup that bound the Skp1–cullin–F-Box (SCF) complex [62].”
From Advances in targeted degradation of endogenous proteins (2019) · cites this paper as [62]
In the citing paper
“This molecule efficiently degraded MetAP-2 in Xenopus oocyte extracts, however it was not cell permeable [62].”
From Advances in targeted degradation of endogenous proteins (2019) · cites this paper as [62]
In the citing paper
“BTRC was efficiently recruited by PROTACs composed of a BTRC-interacting peptide and small-molecule ligands for METAP2, the oestrogen or androgen receptors, leading to degradation of their respective targets 2,113 .”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [2]
Citations
Cites
Phosphorylation meets ubiquitination: the control of NF-κB activity
Karin, M., & Ben-Neriah, Y. (2000) · Annual Review of Immunology · doi:10.1146/annurev.immunol.18.1.621 · Cited by 4,766
IKK-1 and IKK-2: Cytokine-Activated IκB Kinases Essential for NF-κB Activation
Mercurio, F., Zhu, H., Murray, B. W., Shevchenko, A., Bennett, B. L., Li, J. W., Young, D. B., Barbosa, M. S., Mann, M., Manning, A. M., et al. (1997) · Science · doi:10.1126/science.278.5339.860 · Cited by 2,042
Self-citationSCF and Cullin/RING H2-Based Ubiquitin Ligases
Deshaies, R. J. (1999) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.15.1.435 · Cited by 1,238
Self-citationChapter 30 Cell Cycle Extracts
Murray, A. W. (1991) · Methods in cell biology · doi:10.1016/s0091-679x(08)60298-8 · Cited by 942
Epoxomicin, a potent and selective proteasome inhibitor, exhibits in vivo antiinflammatory activity
Meng, L., Mohan, R., Kwok, B. H. B., Elofsson, M., Sin, N., & Crews, C. M. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.18.10403 · Cited by 938
Self-citationNagahara, H., Vocero-Akbani, A. M., Snyder, E. L., Ho, A. L., Latham, D. G., Lissy, N. A., Becker‐Hapak, M., Ezhevsky, S. A., & Dowdy, S. F. (1998) · Nature Medicine · doi:10.1038/4042 · Cited by 928
Ubiquitin-mediated proteolysis: biological regulation via destruction
Ciechanover, A. J., Orian, A., & Schwartz, A. L. (2000) · BioEssays · doi:10.1002/(sici)1521-1878(200005)22:5 · Cited by 848
Margottin-Goguet, F., Bour, S. P., Durand, H., Selig, L., Bénichou, S., Richard, V., Thomas, D., Strebel, K., & Bénarous, R. (1998) · Molecular Cell · doi:10.1016/s1097-2765(00)80056-8 · Cited by 670
Identification of the receptor component of the IκBα–ubiquitin ligase
Yaron, A., Hatzubai, A., Davis, M., Lavon, I., Amit, S., Manning, A. M., Andersen, J., Mann, M., Mercurio, F., & Ben‐Neriah, Y. (1998) · Nature · doi:10.1038/25159 · Cited by 654
Self-citationSin, N., Meng, L., Wang, M. Q. W., Wen, J., Bornmann, W. G., & Crews, C. M. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.12.6099 · Cited by 634
Self-citationStructure of Human Methionine Aminopeptidase-2 Complexed with Fumagillin
Liu, S., Widom, J., Kemp, C. W., Crews, C. M., & Clardy, J. (1998) · Science · doi:10.1126/science.282.5392.1324 · Cited by 440
Self-citationMurray, A. W. (1991) · PubMed · Cited by 438
Printing Small Molecules as Microarrays and Detecting Protein−Ligand Interactions en Masse
MacBeath, G., Koehler, A. N., & Schreiber, S. L. (1999) · Journal of the American Chemical Society · doi:10.1021/ja991083q · Cited by 423
Griffith, E. C., Su, Z., Turk, B. E., Chen, S., Chang, Y., Wu, Z., BIEMANN, K., & Liu, J. O. (1997) · Chemistry & Biology · doi:10.1016/s1074-5521(97)90198-8 · Cited by 421
A family of mammalian F-box proteins
Winston, J. T., Koepp, D. M., Zhu, C., Elledge, S. J., & Harper, J. W. (1999) · Current Biology · doi:10.1016/s0960-9822(00)80021-4 · Cited by 357
Recruitment of a ROC1–CUL1 Ubiquitin Ligase by Skp1 and HOS to Catalyze the Ubiquitination of IκBα
Tan, P., Fuchs, S. Y., Chen, A., Wu, K. K.-Y., Gomez, C., Ronai, Z. A., & Pan, Z. (1999) · Molecular Cell · doi:10.1016/s1097-2765(00)80481-5 · Cited by 345
Li, X., & Chang, Y. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.26.12357 · Cited by 294
Belshaw, P. J., Ho, S. N., Crabtree, G. R., & Schreiber, S. L. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.10.4604 · Cited by 278
Schubert, U., Antón, L. C., Bačík, I., Cox, J. H., Bour, S. P., Bennink, J. R., Orłowski, M., Strebel, K., & Yewdell, J. W. (1998) · Journal of Virology · doi:10.1128/jvi.72.3.2280-2288.1998 · Cited by 258
Inhibition of NF‐κB cellular function via specific targeting of the IκB‐ubiquitin ligase
Yaron, A., Gonen, H., Alkalay, I., Hatzubai, A., Jung, S., Beyth, S., Mercurio, F., Manning, A. M., Ciechanover, A. J., & Ben‐Neriah, Y. (1997) · The EMBO Journal · doi:10.1093/emboj/16.21.6486 · Cited by 239
Self-citationHarnessing the Ubiquitination Machinery to Target the Degradation of Specific Cellular Proteins
Zhou, P., Bogacki, R., McReynolds, L., & Howley, P. M. (2000) · Molecular Cell · doi:10.1016/s1097-2765(00)00074-5 · Cited by 164
Lyapina, S., Correll, C. C., Kipreos, E. T., & Deshaies, R. J. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.13.7451 · Cited by 139
Self-citationThe antiangiogenic agent TNP-470 requires p53 and p21 CIP/WAF for endothelial cell growth arrest
Yeh, J.-R. J., Mohan, R., & Crews, C. M. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.23.12782 · Cited by 120
Self-citationA miniaturized arrayed assay format for detecting small molecule-protein interactions in cells
You, A., Jackman, R. J., Whitesides, G. M., & Schreiber, S. L. (1997) · Chemistry & Biology · doi:10.1016/s1074-5521(97)90305-7 · Cited by 71
Borchardt, A., Liberles, S. D., Biggar, S. R., et al. (1997) · Chemistry & Biology · doi:10.1016/s1074-5521(97)90304-5 · Cited by 58
Cited by
Sorted by citations
PROTAC targeted protein degraders: the past is prologue
Békés, M., Langley, D. R., & Crews, C. M. (2022) · Nature Reviews Drug Discovery · doi:10.1038/s41573-021-00371-6 · Cited by 3,395
Self-citationAn auxin-based degron system for the rapid depletion of proteins in nonplant cells
Nishimura, K., Fukagawa, T., Takisawa, H., Kakimoto, T., & Kanemaki, M. (2009) · Nature Methods · doi:10.1038/nmeth.1401 · Cited by 1,663
Phthalimide conjugation as a strategy for in vivo target protein degradation
Winter, G. E., Buckley, D. L., Paulk, J., Roberts, J. M., Souza, A., Dhe-Paganon, S., & Bradner, J. E. (2015) · Science · doi:10.1126/science.aab1433 · Cited by 1,760
Ubiquitin ligases: structure, function, and regulation
Zheng, N., & Shabek, N. (2017) · Annual Review of Biochemistry · doi:10.1146/annurev-biochem-060815-014922 · Cited by 1,499
Induced protein degradation: an emerging drug discovery paradigm
Lai, A. C., & Crews, C. M. (2017) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.211 · Cited by 1,486
Self-citation
Metadata
- Authors
- Sakamoto, K. M., Kim, K. B., Kumagai, A., Mercurio, F., Crews, C. M., & Deshaies, R. J.
- Affiliations
- California Institute of Technology (US)
- Corresponding author
- Deshaies, Raymond J.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2001-07-03
- Volume
- 98
- Issue
- 15
- Pages
- 8554-8559
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC37474
- OpenAlex
- W2151683271
- Cited by
- 2,609
- References
- 25
- Citations by year
- 2026: 355 · 2025: 435 · 2024: 399 · 2023: 309 · 2022: 278 · 2021: 224 · 2020: 193 · 2019: 118 · 2018: 75 · 2017: 48 · 2016: 28 · 2015: 15 · 2014: 13 · 2013: 9 · 2012: 10
- FWCI
- 2.79
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- Leukemia and Lymphoma Society
- University of California, Los Angeles
- Jonsson Comprehensive Cancer Center
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Physical Sciences › Chemistry › Organic Chemistry › Chemical Synthesis and Analysis
- Keywords
- PROTACs, chimeric molecules, SCF ubiquitin ligase, β-TrCP, ubiquitination, protein degradation, targeted protein degradation
- MeSH terms
- NF-KappaB Inhibitor alpha, Aminopeptidases, Animals, Cell Extracts, Cell Line, Transformed, DNA-Binding Proteins, Humans, Metalloendopeptidases, Ovum, Peptide Synthases, Protein Binding, Recombinant Fusion Proteins, Ubiquitins, Xenopus laevis, I-kappa B Proteins, SKP Cullin F-Box Protein Ligases
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
