4y5y: Difference between revisions
New page: '''Unreleased structure''' The entry 4y5y is ON HOLD Authors: Moraga, I., Guo, F., Ozkan, E., Jude, K.M., Garcia, K.C. Description: Diabody 305 complex with EpoR [[Category: Unreleased... |
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==Diabody 330 complex with EpoR== | |||
<StructureSection load='4y5y' size='340' side='right'caption='[[4y5y]], [[Resolution|resolution]] 2.85Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4y5y]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4Y5Y OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4Y5Y 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]] 2.85Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MLY:N-DIMETHYL-LYSINE'>MLY</scene></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=4y5y FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4y5y OCA], [https://pdbe.org/4y5y PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4y5y RCSB], [https://www.ebi.ac.uk/pdbsum/4y5y PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4y5y 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. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Most cell-surface receptors for cytokines and growth factors signal as dimers, but it is unclear whether remodeling receptor dimer topology is a viable strategy to "tune" signaling output. We utilized diabodies (DA) as surrogate ligands in a prototypical dimeric receptor-ligand system, the cytokine Erythropoietin (EPO) and its receptor (EpoR), to dimerize EpoR ectodomains in non-native architectures. Diabody-induced signaling amplitudes varied from full to minimal agonism, and structures of these DA/EpoR complexes differed in EpoR dimer orientation and proximity. Diabodies also elicited biased or differential activation of signaling pathways and gene expression profiles compared to EPO. Non-signaling diabodies inhibited proliferation of erythroid precursors from patients with a myeloproliferative neoplasm due to a constitutively active JAK2V617F mutation. Thus, intracellular oncogenic mutations causing ligand-independent receptor activation can be counteracted by extracellular ligands that re-orient receptors into inactive dimer topologies. This approach has broad applications for tuning signaling output for many dimeric receptor systems. | |||
Tuning Cytokine Receptor Signaling by Re-orienting Dimer Geometry with Surrogate Ligands.,Moraga I, Wernig G, Wilmes S, Gryshkova V, Richter CP, Hong WJ, Sinha R, Guo F, Fabionar H, Wehrman TS, Krutzik P, Demharter S, Plo I, Weissman IL, Minary P, Majeti R, Constantinescu SN, Piehler J, Garcia KC Cell. 2015 Mar 12;160(6):1196-208. doi: 10.1016/j.cell.2015.02.011. Epub 2015 Feb, 26. PMID:25728669<ref>PMID:25728669</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 4y5y" style="background-color:#fffaf0;"></div> | ||
[[Category: Guo | |||
[[Category: Jude | ==See Also== | ||
[[Category: | *[[Antibody 3D structures|Antibody 3D structures]] | ||
[[Category: | *[[Erythropoietin receptor|Erythropoietin receptor]] | ||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Garcia KC]] | |||
[[Category: Guo F]] | |||
[[Category: Jude KM]] | |||
[[Category: Moraga I]] | |||
[[Category: Ozkan E]] | |||
Latest revision as of 10:54, 27 September 2023
Diabody 330 complex with EpoRDiabody 330 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 PubMedMost cell-surface receptors for cytokines and growth factors signal as dimers, but it is unclear whether remodeling receptor dimer topology is a viable strategy to "tune" signaling output. We utilized diabodies (DA) as surrogate ligands in a prototypical dimeric receptor-ligand system, the cytokine Erythropoietin (EPO) and its receptor (EpoR), to dimerize EpoR ectodomains in non-native architectures. Diabody-induced signaling amplitudes varied from full to minimal agonism, and structures of these DA/EpoR complexes differed in EpoR dimer orientation and proximity. Diabodies also elicited biased or differential activation of signaling pathways and gene expression profiles compared to EPO. Non-signaling diabodies inhibited proliferation of erythroid precursors from patients with a myeloproliferative neoplasm due to a constitutively active JAK2V617F mutation. Thus, intracellular oncogenic mutations causing ligand-independent receptor activation can be counteracted by extracellular ligands that re-orient receptors into inactive dimer topologies. This approach has broad applications for tuning signaling output for many dimeric receptor systems. Tuning Cytokine Receptor Signaling by Re-orienting Dimer Geometry with Surrogate Ligands.,Moraga I, Wernig G, Wilmes S, Gryshkova V, Richter CP, Hong WJ, Sinha R, Guo F, Fabionar H, Wehrman TS, Krutzik P, Demharter S, Plo I, Weissman IL, Minary P, Majeti R, Constantinescu SN, Piehler J, Garcia KC Cell. 2015 Mar 12;160(6):1196-208. doi: 10.1016/j.cell.2015.02.011. Epub 2015 Feb, 26. PMID:25728669[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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