{"doi":"10.1073/pnas.2001683117","title":"Regulation of Cullin-RING E3 ligase dynamics by Inositol hexakisphosphate","abstract":"Perhaps in a decade or so, researchers may look back on current times and view it as an inflection point for the development of novel therapeutic modalities for the treatment of various human diseases. One particularly innovative approach involves targeting disease-modifying proteins for degradation by the proteasome, the large multisubunit protease responsible for the lion's share of regulated protein degradation in human cells (1). The technique uses the action of ubiquitin (UB) ligases, the enzymes that append polyubiquitin chains onto proteins that signal for degradation, and unleashes their activities on disease-causing proteins. Inducing proximity between the ubiquitin ligase and the target is accomplished by small molecule effectors that bind in shallow grooves on both the enzyme and the protein target, acting as “glue” and driving substantial affinities between two proteins that normally do not interact in cells (2, 3). While this may sound more like a futuristic treatment than reality, there are several Food and Drug Administration-approved therapies utilizing induced proximity to target proteins to the proteasome, and even more are in clinical trials (4). While one concern had been that molecular glues capable of promoting protein–protein interactions are quite rare, the study in PNAS by Lin et al. (5) is likely to change opinions on the matter.\n\nBefore explaining the results from Lin et al. (5), a bit of background is necessary. Most of the current therapeutic molecular glues that target disease-causing proteins for degradation utilize the largest family of ubiquitin ligases in humans, the Cullin-RING (Really Interesting New Gene) ligases (CRLs) (6, 7). Some 200 of these enzymes can be found in our cells and account for at least 20% of all proteasome-dependent protein degradation. This grand number of enzymes associates with seven Cullin scaffold proteins, which bind to RING proteins (RBX1/2) that recruit ubiquitin-carrying enzymes. … \n\n[↵][1]1To whom correspondence may be addressed. Email: danny.scott{at}stjude.org.\n\n [1]: #xref-corresp-1-1","journal":"Proceedings of the National Academy of Sciences","year":2020,"id":110380,"datarank":0.4028531045127656,"base_score":1.9459101490553132,"endowment":1.9459101490553132,"self_citation_contribution":0.29188652235829704,"citation_network_contribution":0.11096658215446858,"self_endowment_contribution":0.29188652235829704,"citer_contribution":0.11096658215446858,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":5,"citers_with_citation_signal":4,"citers_with_endowment":4,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9544,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":525391,"name":"Gary Kleiger","orcid":"0000-0003-3924-1680","position":1,"is_corresponding":false},{"id":258414,"name":"Daniel C. Scott","orcid":"0000-0002-7688-5568","position":0,"is_corresponding":true}],"reference_count":25,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:12:57.988348Z","pmid":"32156730","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}