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2jix

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Revision as of 10:09, 18 March 2020

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

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.^[1] ^[2] ^[3]

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^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ de la Chapelle A, Traskelin AL, Juvonen E. Truncated erythropoietin receptor causes dominantly inherited benign human erythrocytosis. Proc Natl Acad Sci U S A. 1993 May 15;90(10):4495-9. PMID:8506290
↑ Sokol L, Prchal JF, D'Andrea A, Rado TA, Prchal JT. Mutation in the negative regulatory element of the erythropoietin receptor gene in a case of sporadic primary polycythemia. Exp Hematol. 1994 May;22(5):447-53. PMID:8174675
↑ Le Couedic JP, Mitjavila MT, Villeval JL, Feger F, Gobert S, Mayeux P, Casadevall N, Vainchenker W. Missense mutation of the erythropoietin receptor is a rare event in human erythroid malignancies. Blood. 1996 Feb 15;87(4):1502-11. PMID:8608241
↑ Liu Z, Stoll VS, Devries PJ, Jakob CG, Xie N, Simmer RL, Lacy SE, Egan DA, Harlan JE, Lesniewski RR, Reilly EB. A potent erythropoietin-mimicking human antibody interacts through a novel binding site. Blood. 2007 Oct 1;110(7):2408-13. Epub 2007 Jul 9. PMID:17620453 doi:10.1182/blood-2007-04-083998

1 Structural highlights
2 Disease
3 Function
4 Evolutionary Conservation
5 Publication Abstract from PubMed
6 See Also
7 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2jix"

@@ Line 1: / Line 1: @@
 ==Crystal structure of ABT-007 FAB fragment with the soluble domain of EPO receptor==
-<StructureSection load='2jix' size='340' side='right' caption='[[2jix]], [[Resolution|resolution]] 3.20&Aring;' scene=''>
+<StructureSection load='2jix' size='340' side='right'caption='[[2jix]], [[Resolution|resolution]] 3.20&Aring;' scene=''>
 == Structural highlights ==
 <table><tr><td colspan='2'>[[2jix]] is a 9 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2JIX OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2JIX FirstGlance]. <br>
@@ Line 39: / Line 39: @@
 </StructureSection>
 [[Category: Human]]
+[[Category: Large Structures]]
 [[Category: DeVries, P]]
 [[Category: Egan, D A]]

2jix

From Proteopedia

Revision as of 10:09, 18 March 2020

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

Structural highlights

Disease

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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