{"doi":"10.1101/2022.08.25.505312","title":"A molecular switch modulates assembly and host factor binding of the HIV-1 capsid","abstract":"Abstract Upon entry into a new host cell, the HIV-1 capsid performs multiple essential functions, which include shielding the genome from innate immune sensors 1 , promoting reverse transcription 2 and transporting the core from the entry site at the plasma membrane to the integration site inside the nucleus 3,4 . The HIV-1 capsid is a fullerene cone made of hexamers and pentamers of the viral CA protein 5,6 . The two types of capsomers are quasi-equivalent, with the same structural elements mediating distinct inter-subunit contacts. In other studied quasi-equivalent viruses, the capacity of genetically identical subunits to form hexamers and pentamers is conferred by molecular switches. Such a switch has not been previously found in retroviral CA proteins. Here, we report cryoEM structures of the HIV-1 CA pentamer within assembled in vitro capsids at nominal resolutions of 2.4-3.4 Å. Comparison with the hexamer identified an internal loop that adopts distinct conformations, 3 10 helix in the pentamer and random coil in the hexamer. Designed manipulations of the coil/helix configuration allowed us to control pentamer and hexamer formation in a predictable manner, thus proving its function as a molecular switch. Importantly, the switch controls not only fullerene cone assembly, but also the capsid’s capacity to bind post-entry host factors that are critical for viral replication. Furthermore, the switch forms part of the binding site of the new ultra-potent HIV-1 inhibitor, lenacapavir. These studies reveal that a critical assembly element also controls the post-assembly functions of the capsid, and provide new insights on capsid inhibition and uncoating.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":296595,"datarank":0.4943755299006494,"base_score":3.295836866004329,"endowment":3.295836866004329,"self_citation_contribution":0.4943755299006494,"citation_network_contribution":0.0,"self_endowment_contribution":0.4943755299006494,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":26,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9501,"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":983465,"name":"Nayara F. B. dos Santos","orcid":"0000-0002-1353-4613","position":1,"is_corresponding":false},{"id":562724,"name":"Kaneil K. Zadrozny","orcid":null,"position":2,"is_corresponding":false},{"id":490073,"name":"Iga Kucharska","orcid":"0000-0001-6150-3419","position":3,"is_corresponding":false},{"id":255582,"name":"Barbie K. Ganser‐Pornillos","orcid":"0000-0001-6453-3891","position":4,"is_corresponding":false},{"id":255584,"name":"Owen Pornillos","orcid":"0000-0001-9056-5002","position":5,"is_corresponding":false},{"id":983464,"name":"Randall T. Schirra","orcid":"0000-0002-7903-0733","position":0,"is_corresponding":true}],"reference_count":48,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T00:31:16.555318Z","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":[]}