{"doi":"10.1016/j.jbc.2024.107438","title":"Three prime repair exonuclease 1 preferentially degrades the integration-incompetent HIV-1 DNA through favorable kinetics, thermodynamic, structural, and conformational properties","abstract":"HIV-1 integration into the human genome is dependent on 3'-processing of the viral DNA. Recently, we reported that the cellular Three Prime Repair Exonuclease 1 (TREX1) enhances HIV-1 integration by degrading the unprocessed viral DNA, while the integration-competent 3'-processed DNA remained resistant. Here, we describe the mechanism by which the 3'-processed HIV-1 DNA resists TREX1-mediated degradation. Our kinetic studies revealed that the rate of cleavage ( k cat ) of the 3'-processed DNA was significantly lower (approximately 2-2.5-fold) than the unprocessed HIV-1 DNA by TREX1. The k cat values of human TREX1 for the processed U5 and U3 DNA substrates were 3.8 s -1 and 4.5 s -1 , respectively. In contrast, the unprocessed U5 and U3 substrates were cleaved at 10.2 s -1 and 9.8 s -1 , respectively. The efficiency of degradation ( k cat /K m ) of the 3'-processed DNA (U5-70.2 and U3-28.05 pM -1 s -1 ) was also significantly lower than the unprocessed DNA (U5-103.1 and U3-65.3 pM -1 s -1 ). Furthermore, the binding affinity (K d ) of TREX1 was markedly lower (∼ 2-fold) for the 3'-processed DNA compared to the unprocessed DNA. Molecular docking and dynamics studies revealed distinct conformational binding modes of TREX1 with the 3'-processed and unprocessed HIV-1 DNA. Particularly, the unprocessed DNA was favorably positioned in the active site with polar interactions with the catalytic residues of TREX1. Additionally, a stable complex was formed between TREX1 and the unprocessed DNA compared the 3'-processed DNA. These results pinpoint the mechanism by which TREX1 preferentially degrades the integration-incompetent HIV-1 DNA and reveal the unique structural and conformational properties of the integration-competent 3'-processed HIV-1 DNA.","journal":"Journal of Biological Chemistry","year":2024,"id":471153,"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":0.9545,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1305735,"name":"Purva Khodke","orcid":"0000-0002-0250-8030","position":1,"is_corresponding":false},{"id":374800,"name":"Muthukumar Balasubramaniam","orcid":"0000-0002-0979-6186","position":2,"is_corresponding":false},{"id":722445,"name":"Benem-Orom Davids","orcid":null,"position":3,"is_corresponding":false},{"id":604632,"name":"Thomas Hollis","orcid":"0000-0002-4996-6346","position":4,"is_corresponding":false},{"id":720867,"name":"Jamaine Davis","orcid":"0000-0002-5078-1306","position":5,"is_corresponding":false},{"id":693919,"name":"Bajarang Vasant Kumbhar","orcid":"0000-0002-3839-9809","position":6,"is_corresponding":false},{"id":374805,"name":"Chandravanu Dash","orcid":"0000-0003-4466-8355","position":7,"is_corresponding":false},{"id":721738,"name":"Prem Prakash","orcid":"0000-0001-6507-7875","position":0,"is_corresponding":true}],"reference_count":70,"raw_metadata":null,"created_at":"2026-07-19T02:05:44.736405Z","pmid":"38838778","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":[]}