{"doi":"10.1073/pnas.2000419117","title":"Interleukin-2 druggability is modulated by global conformational transitions controlled by a helical capping switch","abstract":"Interleukin-2 (IL-2) is a small α-helical cytokine that regulates immune cell homeostasis through its recruitment to a high-affinity heterotrimeric receptor complex (IL-2Rα/IL-2Rβ/γ c ). IL-2 has been shown to have therapeutic efficacy for immune diseases by preferentially expanding distinct T cell compartments, and several regulatory T cell (T reg )-biasing anti–IL-2 antibodies have been developed for combination therapies. The conformational plasticity of IL-2 plays an important role in its biological actions by modulating the strength of receptor and drug interactions. Through an NMR analysis of milliseconds-timescale dynamics of free mouse IL-2 (mIL-2), we identify a global transition to a sparse conformation which is regulated by an α-helical capping “switch” at the loop between the A and B helices (AB loop). Binding to either an anti-mouse IL-2 monoclonal antibody (mAb) or a small molecule inhibitor near the loop induces a measurable response at the core of the structure, while locking the switch to a single conformation through a designed point mutation leads to a global quenching of core dynamics accompanied by a pronounced effect in mAb binding. By elucidating key details of the long-range allosteric communication between the receptor binding surfaces and the core of the IL-2 structure, our results offer a direct blueprint for designing precision therapeutics targeting a continuum of conformational states.","journal":"Proceedings of the National Academy of Sciences","year":2020,"id":75045,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":29,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.954,"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":260360,"name":"Kevin M. Jude","orcid":"0000-0002-3675-5136","position":1,"is_corresponding":false},{"id":58878,"name":"Santrupti Nerli","orcid":"0000-0001-6573-8661","position":2,"is_corresponding":false},{"id":392207,"name":"Caleb R. Glassman","orcid":"0000-0002-3342-7989","position":3,"is_corresponding":false},{"id":218189,"name":"K. Christopher García","orcid":"0000-0001-9273-0278","position":4,"is_corresponding":false},{"id":314926,"name":"Nikolaos G. Sgourakis","orcid":"0000-0003-3655-3902","position":5,"is_corresponding":false},{"id":392206,"name":"Viviane S. De Paula","orcid":"0000-0003-3171-6477","position":0,"is_corresponding":true}],"reference_count":35,"raw_metadata":null,"created_at":"2026-07-18T21:46:33.313355Z","pmid":"32184322","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":[]}