{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Mohan K"],"funding":["Howard Hughes Medical Institute","G Harold and Leila Y. Mathers Foundation","National Institutes of Health"],"pagination":["eaav7532"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC7274355"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["364(6442)"],"pubmed_abstract":["Although tunable signaling by G protein-coupled receptors can be exploited through medicinal chemistry, a comparable pharmacological approach has been lacking for the modulation of signaling through dimeric receptors, such as those for cytokines. We present a strategy to modulate cytokine receptor signaling output by use of a series of designed C2-symmetric cytokine mimetics, based on the designed ankyrin repeat protein (DARPin) scaffold, that can systematically control erythropoietin receptor (EpoR) dimerization orientation and distance between monomers. We sampled a range of EpoR geometries by varying intermonomer angle and distance, corroborated by several ligand-EpoR complex crystal structures. Across the range, we observed full, partial, and biased agonism as well as stage-selective effects on hematopoiesis. This surrogate ligand strategy opens access to pharmacological modulation of therapeutically important cytokine and growth factor receptor systems."],"journal":["Science (New York, N.Y.)"],"pubmed_title":["Topological control of cytokine receptor signaling induces differential effects in hematopoiesis."],"pmcid":["PMC7274355"],"funding_grant_id":["R01 DK103794","R01-AI51321","R33 HL120791","T32HL066987"],"pubmed_authors":["Garcia KC","Guo Y","Sankaran VG","Saxton RA","Baker D","Fallas JA","Piehler J","Mohan K","Hafer M","Jude KM","Kim AR","Miao Y","Ueda G"],"additional_accession":[]},"is_claimable":false,"name":"Topological control of cytokine receptor signaling induces differential effects in hematopoiesis.","description":"Although tunable signaling by G protein-coupled receptors can be exploited through medicinal chemistry, a comparable pharmacological approach has been lacking for the modulation of signaling through dimeric receptors, such as those for cytokines. We present a strategy to modulate cytokine receptor signaling output by use of a series of designed C2-symmetric cytokine mimetics, based on the designed ankyrin repeat protein (DARPin) scaffold, that can systematically control erythropoietin receptor (EpoR) dimerization orientation and distance between monomers. We sampled a range of EpoR geometries by varying intermonomer angle and distance, corroborated by several ligand-EpoR complex crystal structures. Across the range, we observed full, partial, and biased agonism as well as stage-selective effects on hematopoiesis. This surrogate ligand strategy opens access to pharmacological modulation of therapeutically important cytokine and growth factor receptor systems.","dates":{"release":"2019-01-01T00:00:00Z","publication":"2019 May","modification":"2024-11-12T07:19:13.252Z","creation":"2020-06-09T07:14:45Z"},"accession":"S-EPMC7274355","cross_references":{"pubmed":["31123111"],"doi":["10.1126/science.aav7532"]}}