Topological control of cytokine receptor signaling induces differential effects in hematopoiesis

Mohan, Kritika; Ueda, George; Kim, Ah Ram; Jude, Kevin M.; Fallas, Jorge A.; Guo, Yu; Hafer, Maximillian; Miao, Yi; Saxton, Robert A.; Piehler, Jacob; Sankaran, Vijay G.; Baker, David; Garcia, K. Christopher

doi:10.1126/science.aav7532

Title: Topological control of cytokine receptor signaling induces differential effects in hematopoiesis

Journal Article · 22 May 2019 · Science

DOI: https://doi.org/10.1126/science.aav7532 · OSTI ID:1532487

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Stanford Univ., CA (United States). School of Medicine
Univ. of Washington, Seattle, WA (United States). Dept. of Biochemistry, and Inst. for Protein Design
Boston Children’s Hospital and Harvard Medical School, Boston, MA (United States). Division of Hematology/Oncology, The Manton Center for Orphan Disease Research; Harvard Medical School, Boston, MA (United States). Dana-Farber Cancer Inst., Dept. of Pediatric Oncology; Broad Inst. of MIT and Harvard, Cambridge, MA (United States)
Stanford Univ., CA (United States). Howard Hughes Medical Inst.
Nankai Univ., Tianjin (China). State Key Lab. of Medicinal Chemical Biology and College of Pharmacy
Univ. of Osnabrück, Osnabrück (Germany). Division of Biophysics, Dept. of Biology
Stanford Univ., CA (United States). School of Medicine, and Howard Hughes Medical Inst.
Univ. of Osnabrück, Osnabrück (Germany). Division of Biophysics, Dept. of Biology, and Center for Cellular Nanoanalytics
Univ. of Washington, Seattle, WA (United States). Dept. of Biochemistry, and Inst. for Protein Design, and Howard Hughes Medical Inst.
Stanford Univ., CA (United States). School of Medicine, Howard Hughes Medical Inst., and Dept. of Structural Biology

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. Lastly, this surrogate ligand strategy opens access to pharmacological modulation of therapeutically important cytokine and growth factor receptor systems.

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Research Organization:: SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)

Sponsoring Organization:: Deutsche Forschungsgemeinschaft (DFG); National Institutes of Health (NIH); USDOE

Grant/Contract Number:: AC02-05CH11231; AC02-06CH11357; AC02-76SF00515

OSTI ID:: 1532487

Journal Information:: Science, Journal Name: Science Journal Issue: 6442 Vol. 364; ISSN 0036-8075

Publisher:: AAASCopyright Statement

Country of Publication:: United States

Language:: English

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