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PDBsum entry 2jix

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protein Protein-protein interface(s) links
Receptor/immune system PDB id
2jix
Jmol
Contents
Protein chains
214 a.a. *
217 a.a. *
217 a.a. *
* Residue conservation analysis
PDB id:
2jix
Name: Receptor/immune system
Title: Crystal structure of abt-007 fab fragment with the soluble d epo receptor
Structure: Abt-007 fab fragment. Chain: a, g, l. Engineered: yes. Erythropoietin receptor. Chain: b, c, e. Fragment: epo receptor soluble domain, residues 25-249. Synonym: epo-r. Engineered: yes. Abt-007 fab fragment.
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562. Expression_system_taxid: 562
Resolution:
3.20Å     R-factor:   0.260     R-free:   0.323
Authors: Z.Liu,V.S.Stoll,P.Devries,C.G.Jakob,N.Xie,R.L.Simmer,S.E.Lac D.A.Egan,J.E.Harlan,R.R.Lesniewski,E.B.Reilly
Key ref: Z.Liu et al. (2007). A potent erythropoietin-mimicking human antibody interacts through a novel binding site. Blood, 110, 2408-2413. PubMed id: 17620453
Date:
02-Jul-07     Release date:   10-Jul-07    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
Q7Z3Y4  (Q7Z3Y4_HUMAN) -  Uncharacterized protein
Seq:
Struc:
236 a.a.
214 a.a.*
Protein chains
Pfam   ArchSchema ?
P19235  (EPOR_HUMAN) -  Erythropoietin receptor
Seq:
Struc:
508 a.a.
217 a.a.
Protein chains
Pfam   ArchSchema ?
Q6GMX6  (Q6GMX6_HUMAN) -  IGH@ protein
Seq:
Struc:
465 a.a.
217 a.a.*
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 32 residue positions (black crosses)

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     membrane   1 term 
  Biochemical function     cytokine receptor activity     1 term  

 

 
Blood 110:2408-2413 (2007)
PubMed id: 17620453  
 
 
A potent erythropoietin-mimicking human antibody interacts through a novel binding site.
Z.Liu, V.S.Stoll, P.J.Devries, C.G.Jakob, N.Xie, R.L.Simmer, S.E.Lacy, D.A.Egan, J.E.Harlan, R.R.Lesniewski, E.B.Reilly.
 
  ABSTRACT  
 
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.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
  20173635 D.M.Wojchowski, P.Sathyanarayana, and A.Dev (2010).
Erythropoietin receptor response circuits.
  Curr Opin Hematol, 17, 169-176.  
20972421 H.Mao, J.J.Graziano, T.M.Chase, C.A.Bentley, O.A.Bazirgan, N.P.Reddy, B.D.Song, and V.V.Smider (2010).
Spatially addressed combinatorial protein libraries for recombinant antibody discovery and optimization.
  Nat Biotechnol, 28, 1195-1202.  
19223217 M.Perugini, A.Varelias, T.Sadlon, and R.J.D'Andrea (2009).
Hematopoietic growth factor mimetics: from concept to clinic.
  Cytokine Growth Factor Rev, 20, 87-94.  
19264917 P.Sathyanarayana, E.Houde, D.Marshall, A.Volk, D.Makropoulos, C.Emerson, A.Pradeep, P.J.Bugelski, and D.M.Wojchowski (2009).
CNTO 530 functions as a potent EPO mimetic via unique sustained effects on bone marrow proerythroblast pools.
  Blood, 113, 4955-4962.  
  19040789 C.T.Noguchi, L.Wang, H.M.Rogers, R.Teng, and Y.Jia (2008).
Survival and proliferative roles of erythropoietin beyond the erythroid lineage.
  Expert Rev Mol Med, 10, e36.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time.