{"doi":"10.1101/2021.05.03.442258","title":"Structures of the active HER2/HER3 receptor complex reveal dynamics at the dimerization interface induced by binding of a single ligand","abstract":"Abstract The Human Epidermal Growth Factor Receptor 2 (HER2) and HER3 form a potent pro-oncogenic heterocomplex upon binding of growth factor neuregulin-1β (NRG1β) 1–3 . The mechanism by which HER2 and HER3 interact remains unknown in the absence of any structures of the complex. We isolated the NRG1β-bound near full-length HER2/HER3 dimer and obtained a 2.9Å cryo-electron microscopy (cryo-EM) reconstruction of the extracellular domain module which reveals unexpected dynamics at the HER2/HER3 dimerization interface. We show that the dimerization arm of NRG1β-bound HER3 is unresolved likely because the apo HER2 monomer fails to undergo a ligand-induced conformational change needed to establish a HER3 dimerization arm binding pocket. In a second structure of an oncogenic extracellular domain mutant of HER2, S310F, we observe a compensatory interaction with the HER3 dimerization arm that stabilizes the dimerization interface. We show that both HER2/HER3 and HER2-S310F/HER3 retain the capacity to bind to the HER2-directed therapeutic antibody, trastuzumab, but the mutant complex does not bind to pertuzumab. Our 3.5Å structure of the HER2-S310F/HER3/NRG1β/trastuzumab Fragment antigen binding (Fab) complex shows that the receptor dimer undergoes a conformational change to accommodate trastuzumab. Thus, like oncogenic mutations, therapeutics exploit the intrinsic dynamics of the HER2/HER3 heterodimer. The unique features of a singly liganded HER2/HER3 heterodimer underscore the allosteric sensing of the ligand occupancy by the dimerization interface and explain why extracellular domains of HER2 do not homo-associate via canonical active dimer interface.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":218656,"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":0.9408,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":103690,"name":"Raphael Trenker","orcid":"0000-0003-1748-0517","position":1,"is_corresponding":false},{"id":699147,"name":"Tarjani Thaker","orcid":"0000-0002-0947-6094","position":2,"is_corresponding":false},{"id":268593,"name":"Feng Wang","orcid":"0000-0002-1233-2745","position":3,"is_corresponding":false},{"id":98189,"name":"David A. Agard","orcid":"0000-0003-3512-695X","position":4,"is_corresponding":false},{"id":1486,"name":"Kliment A. Verba","orcid":"0000-0002-2238-8590","position":5,"is_corresponding":false},{"id":1485,"name":"Natalia Jura","orcid":"0000-0001-5129-641X","position":6,"is_corresponding":false},{"id":108124,"name":"Devan Diwanji","orcid":"0000-0002-4285-435X","position":0,"is_corresponding":true}],"reference_count":52,"raw_metadata":null,"created_at":"2026-07-18T23:53:29.626149Z","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":[]}