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PDBsum entry 1kvf
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De novo protein
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PDB id
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1kvf
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References listed in PDB file
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Key reference
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Title
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Amino acid determinants of beta-Hairpin conformation in erythropoeitin receptor agonist peptides derived from a phage display library.
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Authors
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N.J.Skelton,
S.Russell,
F.De sauvage,
A.G.Cochran.
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Ref.
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J Mol Biol, 2002,
316,
1111-1125.
[DOI no: ]
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PubMed id
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Abstract
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Display of peptide libraries on filamentous phage has led to the identification
of peptides of the form X(2-5)CX(2)GPXTWXCX(2-5) (where X is a variable residue)
that bind to the extra-cellular portion of the erythropoietin receptor (EPO-R).
These peptides adopt beta-hairpin conformations when co-crystallized with EPO-R.
Solution NMR studies reveal that the peptide is conformationally heterogeneous
in the absence of receptor due to cis-trans isomerization about the Gly-Pro
peptide bond. Replacement of the conserved threonine residue with glycine at the
turn i+3 position produces a stable beta-hairpin conformation in solution,
although this peptide no longer has activity in an EPO-R-dependent cell
proliferation assay. A truncated form of the EPO-R-binding peptide (containing
the i+3 glycine residue) also forms a highly populated, monomeric beta-hairpin.
In contrast, phage-derived peptide antagonists of insulin-like growth factor
binding protein 1 (IGFBP-1) have a high level of sequence identity with the
truncated EPO-R peptide (eight of 12 residues) yet adopt a turn-alpha-helix
conformation in solution. Peptides containing all possible pairwise amino acid
substitutions between the EPO-R and IGFBP-1 peptides have been analyzed to
assess the degree to which the non-conserved residues stabilize the hairpin or
helix conformation. All four residues present in the original sequence are
required for maximum population of either the beta-hairpin or alpha-helix
conformation, although some substitutions have a more dominant effect. The
results demonstrate that, within a given sequence, the observed conformation can
be dictated by a small subset of the residues (in this case four out of 12).
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Figure 6.
Figure 6. Comparison of the crystal structure of
EPO-R-bound EMP-1 with EMP-18b and EPO-3 in solution. The
minimized mean structures of EMP-18b (green) and EPO-3 (cyan)
were superimposed on the crystal structure (pink; PDB accession
code 1ebp chain D) using the N, C^a and C atoms of residues
Cys2-Phe4 and Trp9 to Cys11 (EPO-3 numbering). The C^a of the
residues corresponding to Phe4 and Trp9 of EPO-3 are shown as
spheres, and the carbonyl oxygen atoms of the turn residues are
colored red. The EPO-R atoms that donate a hydrogen bond to the
peptide EMP-1 in the complex are indicated.
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Figure 8.
Figure 8. Structural comparison of EPO-3 and EPO-4. (a)
Minimized mean structure of EPO-3. For the case of Phe4 and
Trp9, two representative side-chain conformations from the
ensemble are depicted (see the text). (b) Minimized mean
structure of EPO-4. For clarity, the side-chain atoms of Ser1
and Lys12 are omitted.
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2002,
316,
1111-1125)
copyright 2002.
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Secondary reference #1
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Title
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Identification of a 13 amino acid peptide mimetic of erythropoietin and description of amino acids critical for the mimetic activity of emp1.
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Authors
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D.L.Johnson,
F.X.Farrell,
F.P.Barbone,
F.J.Mcmahon,
J.Tullai,
K.Hoey,
O.Livnah,
N.C.Wrighton,
S.A.Middleton,
D.A.Loughney,
E.A.Stura,
W.J.Dower,
L.S.Mulcahy,
I.A.Wilson,
L.K.Jolliffe.
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Ref.
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Biochemistry, 1998,
37,
3699-3710.
[DOI no: ]
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PubMed id
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