2jix
From Proteopedia
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==Overview== | ==Overview== | ||
| - | Recombinant human erythropoietin (rHu-EPO) is used to treat anemia by | + | 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. |
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| + | ==Disease== | ||
| + | Known disease associated with this structure: Erythrocytosis, familial OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=133171 133171]] | ||
==About this Structure== | ==About this Structure== | ||
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[[Category: Protein complex]] | [[Category: Protein complex]] | ||
[[Category: Devries, P.]] | [[Category: Devries, P.]] | ||
| - | [[Category: Egan, D | + | [[Category: Egan, D A.]] |
| - | [[Category: Harlan, J | + | [[Category: Harlan, J E.]] |
| - | [[Category: Jakob, C | + | [[Category: Jakob, C G.]] |
| - | [[Category: Lacy, S | + | [[Category: Lacy, S E.]] |
| - | [[Category: Lesniewski, R | + | [[Category: Lesniewski, R R.]] |
[[Category: Liu, Z.]] | [[Category: Liu, Z.]] | ||
| - | [[Category: Reilly, E | + | [[Category: Reilly, E B.]] |
| - | [[Category: Simmer, R | + | [[Category: Simmer, R L.]] |
| - | [[Category: Stoll, V | + | [[Category: Stoll, V S.]] |
[[Category: Xie, N.]] | [[Category: Xie, N.]] | ||
[[Category: abt-007 fab fragment]] | [[Category: abt-007 fab fragment]] | ||
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[[Category: ubl conjugation]] | [[Category: ubl conjugation]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 18:04:08 2008'' |
Revision as of 16:04, 21 February 2008
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CRYSTAL STRUCTURE OF ABT-007 FAB FRAGMENT WITH THE SOLUBLE DOMAIN OF EPO RECEPTOR
Contents |
Overview
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.
Disease
Known disease associated with this structure: Erythrocytosis, familial OMIM:[133171]
About this Structure
2JIX is a Protein complex structure of sequences from Escherichia coli. Full crystallographic information is available from OCA.
Reference
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
Page seeded by OCA on Thu Feb 21 18:04:08 2008
Categories: Escherichia coli | Protein complex | Devries, P. | Egan, D A. | Harlan, J E. | Jakob, C G. | Lacy, S E. | Lesniewski, R R. | Liu, Z. | Reilly, E B. | Simmer, R L. | Stoll, V S. | Xie, N. | Abt-007 fab fragment | Alternative splicing | Antibody | Disease mutation | Epo receptor soluble domain | Glycoprotein | Immune system | Membrane | Phosphorylation | Receptor | Receptor/immune system complex | Signal | Transmembrane | Ubl conjugation
