{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,7]],"date-time":"2025-11-07T19:21:58Z","timestamp":1762543318505,"version":"3.41.2"},"reference-count":43,"publisher":"The Endocrine Society","issue":"2","license":[{"start":{"date-parts":[[2020,11,26]],"date-time":"2020-11-26T00:00:00Z","timestamp":1606348800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["DK11794","AR066261"],"award-info":[{"award-number":["DK11794","AR066261"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Amolyt Pharma"},{"DOI":"10.13039\/100005294","name":"Massachusetts General Hospital","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005294","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,2,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>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\u201334) resulted in marked (~20-fold) reductions in binding affinity on the PTH receptor-1 (PTHR1) in cell membranes, similarly diminished potency for 3\u2032,5\u2032-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\u201334) is situated within the orthosteric ligand-binding pocket of the receptor\u2019s transmembrane domain bundle (TMD), the Met8 sidechain position is shifted for the 2 ligands so that on Met8 oxidation of PTH(1\u201334), steric clashes occur that are not seen with oxidized LA-PTH. The findings suggest that LA-PTH and PTH(1\u201334) 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.<\/jats:p>","DOI":"10.1210\/endocr\/bqaa216","type":"journal-article","created":{"date-parts":[[2020,11,26]],"date-time":"2020-11-26T18:55:51Z","timestamp":1606416951000},"source":"Crossref","is-referenced-by-count":6,"title":["Ligand-Dependent Effects of Methionine-8 Oxidation in Parathyroid Hormone Peptide Analogues"],"prefix":"10.1210","volume":"162","author":[{"given":"Eileen J","family":"Daley","sequence":"first","affiliation":[{"name":"Massachusetts General Hospital and Harvard Medical School, Endocrine Unit, Massachusetts General Hospital, Boston, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ashok","family":"Khatri","sequence":"additional","affiliation":[{"name":"Massachusetts General Hospital and Harvard Medical School, Endocrine Unit, Massachusetts General Hospital, Boston, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Dean","sequence":"additional","affiliation":[{"name":"Massachusetts General Hospital and Harvard Medical School, Endocrine Unit, Massachusetts General Hospital, Boston, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jean-Pierre","family":"Vilardaga","sequence":"additional","affiliation":[{"name":"University of Pittsburgh School of Medicine, Department of Pharmacology & Chemical Biology, Laboratory for GPCR Biology, Pittsburgh, PA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Saheem A","family":"Zaidi","sequence":"additional","affiliation":[{"name":"Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vsevolod","family":"Katritch","sequence":"additional","affiliation":[{"name":"Department of Quantitative and Computational Biology, 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