{"doi":"10.1126/science.aay4919","title":"Structural basis of second-generation HIV integrase inhibitor action and viral resistance","abstract":"Although second-generation HIV integrase strand-transfer inhibitors (INSTIs) are prescribed throughout the world, the mechanistic basis for the superiority of these drugs is poorly understood. We used single-particle cryo-electron microscopy to visualize the mode of action of the advanced INSTIs dolutegravir and bictegravir at near-atomic resolution. Glutamine-148→histidine (Q148H) and glycine-140→serine (G140S) amino acid substitutions in integrase that result in clinical INSTI failure perturb optimal magnesium ion coordination in the enzyme active site. The expanded chemical scaffolds of second-generation compounds mediate interactions with the protein backbone that are critical for antagonizing viruses containing the Q148H and G140S mutations. Our results reveal that binding to magnesium ions underpins a fundamental weakness of the INSTI pharmacophore that is exploited by the virus to engender resistance and provide a structural framework for the development of this class of anti-HIV/AIDS therapeutics.","journal":"Science","year":2020,"id":54152,"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":107,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9619,"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":277724,"name":"Wen Li","orcid":"0000-0003-0197-0933","position":1,"is_corresponding":false},{"id":36707,"name":"Denes Berta","orcid":"0000-0002-8299-3784","position":2,"is_corresponding":false},{"id":277725,"name":"Magd Badaoui","orcid":"0000-0001-9521-6696","position":3,"is_corresponding":false},{"id":277726,"name":"Allison Ballandras-Colas","orcid":"0000-0003-4735-4984","position":4,"is_corresponding":false},{"id":277727,"name":"Andrea Nans","orcid":"0000-0002-3791-2447","position":5,"is_corresponding":false},{"id":277728,"name":"Abhay Kotecha","orcid":"0000-0002-4480-5439","position":6,"is_corresponding":false},{"id":36775,"name":"Edina Rosta","orcid":"0000-0002-9823-4766","position":7,"is_corresponding":false},{"id":228712,"name":"Alan Engelman","orcid":"0000-0002-9709-2591","position":8,"is_corresponding":false},{"id":277729,"name":"Peter Cherepanov","orcid":"0000-0002-0634-538X","position":9,"is_corresponding":false},{"id":277723,"name":"Nicola Cook","orcid":"0000-0002-2738-7976","position":0,"is_corresponding":true}],"reference_count":64,"raw_metadata":null,"created_at":"2026-07-18T21:03:43.037640Z","pmid":"32001525","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":[]}