2jix

Crystal structure of ABT-007 FAB fragment with the soluble domain of EPO receptor

spinqualitylabelsall models 2jix, resolution 3.20Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 2jix is a 9 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Related: 1cn4, 1eba, 1ebp, 1eer, 1ern Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease [EPOR_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. Function [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. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed Recombinant human erythropoietin (rHu-EPO) is used to treat anemia by activating the erythropoietin receptor (EPOR) in erythroid progenitor cells, leading to proliferation and differentiation into mature red blood cells. To allow less frequent dosing, a hyperglycosylated version of EPO has been developed with a longer half-life. In principle, an agonistic antibody targeting EPOR would offer an even longer half-life, support robust monthly dosing, and, unlike EPO products, reduce the risk of pure red cell aplasia. The efficiency of signaling and corresponding potency of previously reported antibody mimics are generally suboptimal compared with EPO and not suitable for clinical use. Here we describe a potent, fully human, agonistic antibody (ABT007) targeting EPOR that supports potent, more sustained, and less pulsatile elevation of hematocrit in a human EPOR-expressing transgenic mouse model compared with standard doses of rHu-EPO while requiring less frequent dosing. Resolution of the crystal structure of the EPOR extracellular domain (ECD) complexed to the ABT007 Fab fragment, determined at 0.32 nm, identifies a binding site that is consistent with a novel mechanism of receptor activation based on a unique antibody-imposed conformational change. These results demonstrate that a symmetric molecule can serve as a potent activator of the EPOR. A potent erythropoietin-mimicking human antibody interacts through a novel binding site.,Liu Z, Stoll VS, Devries PJ, Jakob CG, Xie N, Simmer RL, Lacy SE, Egan DA, Harlan JE, Lesniewski RR, Reilly EB Blood. 2007 Oct 1;110(7):2408-13. Epub 2007 Jul 9. PMID:17620453 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Antibody 3D structures Erythropoietin receptor

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