{"doi":"10.1210/endocr/bqaa216","title":"Ligand-Dependent Effects of Methionine-8 Oxidation in Parathyroid Hormone Peptide Analogues","abstract":"LA-PTH is a long-acting parathyroid hormone (PTH) peptide analogue in preclinical development for hypoparathyroidism (HP). Like native PTH, LA-PTH contains a methionine at position 8 (Met8) that is predicted to be critical for function. We assessed the impact of Met oxidation on the functional properties of LA-PTH and control PTH ligands. Oxidation of PTH(1-34) resulted in marked (~20-fold) reductions in binding affinity on the PTH receptor-1 (PTHR1) in cell membranes, similarly diminished potency for 3',5'-cyclic AMP signaling in osteoblastic cell lines (SaOS-2 and UMR106), and impaired efficacy for raising blood calcium in mice. Surprisingly, oxidation of LA-PTH resulted in little or no change in these functional responses. The signaling potency of oxidized-LA-PTH was, however, reduced approximately 40-fold compared to LA-PTH in cells expressing a PTHR1 construct that lacks the N-terminal extracellular domain (ECD). Molecular modeling revealed that while Met8 of both LA-PTH and PTH(1-34) is situated within the orthosteric ligand-binding pocket of the receptor's transmembrane domain bundle (TMD), the Met8 sidechain position is shifted for the 2 ligands so that on Met8 oxidation of PTH(1-34), steric clashes occur that are not seen with oxidized LA-PTH. The findings suggest that LA-PTH and PTH(1-34) engage the receptor differently in the Met8-interaction environment of the TMD bundle, and that this interaction environment can be allosterically influenced by the ECD component of the ligand-receptor complex. The findings should be useful for the future development of novel PTH-based peptide therapeutics for diseases of bone and mineral ion metabolism.","journal":"Endocrinology","year":2020,"id":106902,"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":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9597,"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":108426,"name":"Ashok Khatri","orcid":"0000-0003-4740-3846","position":1,"is_corresponding":false},{"id":341571,"name":"Thomas Dean","orcid":"0000-0001-9065-0784","position":2,"is_corresponding":false},{"id":281860,"name":"Jean‐Pierre Vilardaga","orcid":"0000-0002-1217-1435","position":3,"is_corresponding":false},{"id":514936,"name":"Saheem A. Zaidi","orcid":"0000-0001-7531-3587","position":4,"is_corresponding":false},{"id":40489,"name":"Vsevolod Katritch","orcid":"0000-0003-3883-4505","position":5,"is_corresponding":false},{"id":311402,"name":"Thomas J. Gardella","orcid":"0000-0002-2163-5772","position":6,"is_corresponding":false},{"id":313010,"name":"Eileen J. Daley","orcid":null,"position":0,"is_corresponding":true}],"reference_count":46,"raw_metadata":null,"created_at":"2026-07-18T23:12:31.053776Z","pmid":"33242090","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":[]}