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PDBsum entry 2jix
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Receptor/immune system
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PDB id
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2jix
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Contents |
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214 a.a.
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217 a.a.
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217 a.a.
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* Residue conservation analysis
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PDB id:
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Receptor/immune system
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Title:
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Crystal structure of abt-007 fab fragment with the soluble domain of epo receptor
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Structure:
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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.
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562. Expression_system_taxid: 562
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Resolution:
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3.20Å
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R-factor:
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0.260
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R-free:
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0.323
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Authors:
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Z.Liu,V.S.Stoll,P.Devries,C.G.Jakob,N.Xie,R.L.Simmer,S.E.Lacy, D.A.Egan,J.E.Harlan,R.R.Lesniewski,E.B.Reilly
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Key ref:
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Z.Liu
et al.
(2007).
A potent erythropoietin-mimicking human antibody interacts through a novel binding site.
Blood,
110,
2408-2413.
PubMed id:
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Date:
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02-Jul-07
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Release date:
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10-Jul-07
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PROCHECK
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Headers
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References
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Q7Z3Y4
(Q7Z3Y4_HUMAN) -
Ig-like domain-containing protein from Homo sapiens
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Seq:
Struc:
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236 a.a.
214 a.a.*
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Blood
110:2408-2413
(2007)
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PubMed id:
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A potent erythropoietin-mimicking human antibody interacts through a novel binding site.
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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.
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ABSTRACT
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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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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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D.M.Wojchowski,
P.Sathyanarayana,
and
A.Dev
(2010).
Erythropoietin receptor response circuits.
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Curr Opin Hematol,
17,
169-176.
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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.
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Nat Biotechnol,
28,
1195-1202.
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M.Perugini,
A.Varelias,
T.Sadlon,
and
R.J.D'Andrea
(2009).
Hematopoietic growth factor mimetics: from concept to clinic.
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Cytokine Growth Factor Rev,
20,
87-94.
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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.
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Blood,
113,
4955-4962.
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C.T.Noguchi,
L.Wang,
H.M.Rogers,
R.Teng,
and
Y.Jia
(2008).
Survival and proliferative roles of erythropoietin beyond the erythroid lineage.
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Expert Rev Mol Med,
10,
e36.
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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.
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Links
