{"doi":"10.1101/2022.07.27.501640","title":"Cryptochrome-Timeless structure reveals circadian clock timing mechanisms","abstract":"Circadian rhythms influence many behaviors and diseases 1, 2 . They arise from oscillations in gene expression caused by repressor proteins that directly inhibit transcription of their own genes. The fly circadian clock offers a valuable model for studying these processes, wherein Timeless (TIM) plays a critical role in mediating nuclear entry of the transcriptional repressor Period (PER) and the photoreceptor Cryptochrome (CRY) entrains the clock by triggering TIM degradation in light 2, 3 . The cryo-EM structure of the CRY:TIM complex reveals how a light-sensing cryptochrome recognizes its target. CRY engages a continuous core of N-terminal TIM armadillo (ARM) repeats, resembling how photolyases recognize damaged DNA, and binds a C-terminal TIM helix reminiscent of the interactions between light-insensitive CRYs and their partners in mammals. The structure highlights how the CRY flavin cofactor undergoes conformational changes that couple to large-scale rearrangements at the molecular interface, and how a phosphorylated segment in TIM may impact clock period by regulating the binding of importin-α and the nuclear import of TIM:PER 4, 5 . Moreover, the structure reveals that the TIM N-terminus inserts into the restructured CRY pocket to replace the autoinhibitory C-terminal tail released by light, thereby providing a possible explanation for how the LS-TIM polymorphism adapts flies to different climates 6, 7 .","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":301619,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9566,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":992741,"name":"Shi Feng","orcid":"0000-0001-9084-3957","position":1,"is_corresponding":false},{"id":678558,"name":"Cristina C. DeOliveira","orcid":"0000-0002-1666-5934","position":2,"is_corresponding":false},{"id":401781,"name":"Brian R. Crane","orcid":"0000-0001-8234-9991","position":3,"is_corresponding":false},{"id":678557,"name":"Changfan Lin","orcid":"0000-0002-8119-9845","position":0,"is_corresponding":true}],"reference_count":65,"raw_metadata":null,"created_at":"2026-07-19T00:32:02.193874Z","pmid":null,"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":[]}