View source for 6mok


==Dimeric DARPin A_distance_R7 complex with EpoR==
<StructureSection load='6mok' size='340' side='right'caption='[[6mok]], [[Resolution|resolution]] 5.10&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6mok]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6MOK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6MOK FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 5.101&#8491;</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6mok FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6mok OCA], [https://pdbe.org/6mok PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6mok RCSB], [https://www.ebi.ac.uk/pdbsum/6mok PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6mok ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/EPOR_HUMAN EPOR_HUMAN] Defects in EPOR are the cause of familial erythrocytosis type 1 (ECYT1) [MIM:[https://omim.org/entry/133100 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.<ref>PMID:8506290</ref> <ref>PMID:8174675</ref> <ref>PMID:8608241</ref> 
== Function ==
[https://www.uniprot.org/uniprot/EPOR_HUMAN EPOR_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.
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== Publication Abstract from PubMed ==
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.

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<ref>PMID:31123111</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6mok" style="background-color:#fffaf0;"></div>

==See Also==
*[[Erythropoietin receptor|Erythropoietin receptor]]
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Synthetic construct]]
[[Category: Garcia KC]]
[[Category: Guo Y]]
[[Category: Jude KM]]
[[Category: Mohan K]]