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There is intense interest in understanding how variation in GPCR ligand structure can be used to promote pathway selective signaling (\u201cbiased agonism\u201d) with the goal of promoting desirable responses and avoiding deleterious side effects. Here we present an approach in which a conventional peptide ligand for the type 1 parathyroid hormone receptor (PTHR1) is converted from an agonist which induces signaling through all relevant pathways to a compound that is highly selective for a single pathway. This is achieved not through variation in the core structure of the agonist, but rather by linking it to a nanobody tethering agent that binds with high affinity to a separate site on the receptor not involved in signal transduction. The resulting conjugate represents the most biased agonist of PTHR1 reported to date. This approach holds promise for facile generation of pathway selective ligands for other GPCRs.<\/jats:p>","DOI":"10.1038\/s41467-024-49068-5","type":"journal-article","created":{"date-parts":[[2024,6,1]],"date-time":"2024-06-01T16:01:54Z","timestamp":1717257714000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["Highly biased agonism for GPCR ligands via nanobody tethering"],"prefix":"10.1038","volume":"15","author":[{"given":"Shivani","family":"Sachdev","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brendan A.","family":"Creemer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas J.","family":"Gardella","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9871-8333","authenticated-orcid":false,"given":"Ross W.","family":"Cheloha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,6,1]]},"reference":[{"key":"49068_CR1","doi-asserted-by":"publisher","first-page":"897","DOI":"10.1146\/annurev-biochem-060614-033910","volume":"87","author":"WI Weis","year":"2018","unstructured":"Weis, W. 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