{"doi":"10.1101/2022.05.03.490500","title":"Structures of NF-κB p52 homodimer-DNA complexes rationalize binding mechanisms and transcription activation","abstract":"Abstract The mammalian NF-κB p52:p52 homodimer together with its cofactor Bcl3 activates transcription of κB sites with a central G/C base pair (bp), while it is inactive toward κB sites with a central A/T bp. To understand the molecular basis for this unique property of p52, we have determined its structure in complex with a P-selectin(PSel)-κB DNA (5’-GGGGT G ACCCC-3’) (central bp is underlined) and variants changing the central bp to A/T or swapping the flanking bp. The structures reveal a nearly two-fold widened minor groove in the central region of the DNA as compared to all other currently available NF-κB-DNA complex structures, which have a central A/T bp. Molecular dynamics (MD) simulations show free DNAs exist in distinct preferred conformations, and p52:p52 homodimer induces the least amount of conformational changes on the more transcriptionally active natural PSel-κB DNA in the bound form. Our binding assays further demonstrate that the fast kinetics driven by entropy is correlated with higher transcriptional activity. Overall, our studies have revealed a novel conformation for κB DNA in complex with NF-κB and suggest the importance of binding kinetics, dictated by free DNA conformational and dynamic states, in controlling transcriptional activation for NF-κB.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":307921,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9576,"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":883946,"name":"Wenfei Pan","orcid":null,"position":1,"is_corresponding":false},{"id":1002412,"name":"Tianjie Li","orcid":"0000-0003-4734-1577","position":2,"is_corresponding":false},{"id":1002413,"name":"Yi Wang","orcid":"0000-0002-4174-8790","position":3,"is_corresponding":false},{"id":304202,"name":"Gourisankar Ghosh","orcid":"0000-0001-6311-7351","position":4,"is_corresponding":false},{"id":667665,"name":"Vivien Ya‐Fan Wang","orcid":"0000-0002-1984-2713","position":5,"is_corresponding":false},{"id":1002411,"name":"V. A. Meshcheryakov","orcid":"0000-0001-8471-1544","position":0,"is_corresponding":true}],"reference_count":62,"raw_metadata":null,"created_at":"2026-07-19T00:33:00.101913Z","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":[]}