Journal
SCIENCE
Volume 364, Issue 6442, Pages 750-+Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aav7532
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Funding
- NIH [R01-AI51321, T32HL066987, R01 DK103794, R33 HL120791, S10OD021832]
- Deutsche Forschungsgemeinschaft (DFG) [SFB 944]
- Howard Hughes Medical Institute (HHMI)
- National Cancer Institute [ACB-12002]
- National Institute of General Medical Sciences (NIGMS) [AGM-12006]
- DOE Office of Science [DE-AC02-06CH11357]
- NIH-Office of Research Infrastructure Programs, High-End Instrumentation Grant [1S10OD012289-01A1]
- HHMI
- DOE Office of Science User Facility [DE-AC02-05CH11231]
- DOE Office of Science, Office of Basic Energy Sciences [DE-AC02-76SF00515]
- DOE Office of Biological and Environmental Research
- NIGMS [P41GM103393]
- Mathers Fund
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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-EpoRcomplex 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.
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