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PDBsum entry 1ern
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Crystallographic evidence for preformed dimers of erythropoietin receptor before ligand activation.
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Authors
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O.Livnah,
E.A.Stura,
S.A.Middleton,
D.L.Johnson,
L.K.Jolliffe,
I.A.Wilson.
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Ref.
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Science, 1999,
283,
987-990.
[DOI no: ]
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PubMed id
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Abstract
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Erythropoietin receptor (EPOR) is thought to be activated by ligand-induced
homodimerization. However, structures of agonist and antagonist peptide
complexes of EPOR, as well as an EPO-EPOR complex, have shown that the actual
dimer configuration is critical for the biological response and signal
efficiency. The crystal structure of the extracellular domain of EPOR in its
unliganded form at 2.4 angstrom resolution has revealed a dimer in which the
individual membrane-spanning and intracellular domains would be too far apart to
permit phosphorylation by JAK2. This unliganded EPOR dimer is formed from
self-association of the same key binding site residues that interact with
EPO-mimetic peptide and EPO ligands. This model for a preformed dimer on the
cell surface provides insights into the organization, activation, and plasticity
of recognition of hematopoietic cell surface receptors.
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Figure 1.
Fig. 1. Comparison of the unliganded and liganded EPOR
receptor dimer configurations. (A) A schematic representation of
the quaternary structure of the native EBP dimer. The two EBP
molecules form a cross-like self dimer and are shown in cyan and
gold, with their individual domains labeled D1 and D2. A close,
symmetrical interaction is formed between the two EBP molecules
on the basis of their previously determined ligand-binding
epitope regions (11). The three-residue linker between the
NH[2]-terminal  helix and
the FBN-III domains in both molecules is omitted because of the
lack of electron density in this region and the NH[2]-terminal
helices
are omitted for clarity. The D1 domains of each monomer point in
opposite directions, whereas the two D2 domains can both be
aligned toward the membrane with a rotation of 135° between
them. The membrane-proximal ends of D2 in each molecule (Thr220)
are shown by a black arrow emphasizing the 73 Å separation
between them. In the schematic of the unliganded self dimer
(right), the different scissors-like dimer configuration keeps
the intracellular ends far enough apart such that
autophosphorylation of JAK-2 cannot occur and hence other
phosphorylation events, such as on the cytoplasmic domain of the
EPOR, do not occur. (B) The quaternary structure of the EBP-EMP1
complex. The two EBP molecules are shown in gold and cyan and
the EMP1 dimer in purple. Two EMP1 peptides bind to two EBP
receptor molecules in a symmetrical manner (11). The domains are
labeled in D1 and D2 and the equivalent COOH-terminal
membrane-proximal ends of each receptor are shown by black
arrows that highlight the difference in distances and receptor
dimer configurations for the unliganded native and
EMP1-complexed EBPs. In the schematic of the liganded form
(right), EMP1 [or EPO (13)] induces a close dimer association of
both the D1 and D2 domains so that their intracellular regions
become substrates for phosphorylation by two JAK-2 molecules.
The stick figures were made with MIDAS (30).
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The above figure is
reprinted
by permission from the AAAs:
Science
(1999,
283,
987-990)
copyright 1999.
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Secondary reference #1
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Title
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Functional mimicry of a protein hormone by a peptide agonist: the epo receptor complex at 2.8 a.
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Authors
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O.Livnah,
E.A.Stura,
D.L.Johnson,
S.A.Middleton,
L.S.Mulcahy,
N.C.Wrighton,
W.J.Dower,
L.K.Jolliffe,
I.A.Wilson.
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Ref.
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Science, 1996,
273,
464-471.
[DOI no: ]
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PubMed id
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