6moj
Dimeric DARPin A_angle_R5 complex with EpoR
Structural highlights
DiseaseEPOR_HUMAN Defects in EPOR are the cause of familial erythrocytosis type 1 (ECYT1) [MIM:133100. ECYT1 is an autosomal dominant disorder characterized by increased serum red blood cell mass, elevated hemoglobin and hematocrit, hypersensitivity of erythroid progenitors to erythropoietin, erythropoietin low serum levels, and no increase in platelets nor leukocytes. It has a relatively benign course and does not progress to leukemia.[1] [2] [3] FunctionEPOR_HUMAN Receptor for erythropoietin. Mediates erythropoietin-induced erythroblast proliferation and differentiation. Upon EPO stimulation, EPOR dimerizes triggering the JAK2/STAT5 signaling cascade. In some cell types, can also activate STAT1 and STAT3. May also activate the LYN tyrosine kinase. Isoform EPOR-T acts as a dominant-negative receptor of EPOR-mediated signaling. Publication Abstract from PubMedAlthough 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. Topological control of cytokine receptor signaling induces differential effects in hematopoiesis.,Mohan K, Ueda G, Kim AR, Jude KM, Fallas JA, Guo Y, Hafer M, Miao Y, Saxton RA, Piehler J, Sankaran VG, Baker D, Garcia KC Science. 2019 May 24;364(6442). pii: 364/6442/eaav7532. doi:, 10.1126/science.aav7532. Epub 2019 May 23. PMID:31123111[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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