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PDBsum entry 3c3h
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De novo protein
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PDB id
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3c3h
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References listed in PDB file
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Key reference
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Title
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Interplay among side chain sequence, Backbone composition, And residue rigidification in polypeptide folding and assembly.
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Authors
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W.S.Horne,
J.L.Price,
S.H.Gellman.
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Ref.
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Proc Natl Acad Sci U S A, 2008,
105,
9151-9156.
[DOI no: ]
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PubMed id
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Abstract
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The extent to which polypeptide conformation depends on side-chain composition
and sequence has been widely studied, but less is known about the importance of
maintaining an alpha-amino acid backbone. Here, we examine a series of peptides
with backbones that feature different repeating patterns of alpha- and
beta-amino acid residues but an invariant side-chain sequence. In the pure
alpha-backbone, this sequence corresponds to the previously studied peptide
GCN4-pLI, which forms a very stable four-helix bundle quaternary structure.
Physical characterization in solution and crystallographic structure
determination show that a variety of alpha/beta-peptide backbones can adopt
sequence-encoded quaternary structures similar to that of the alpha prototype.
There is a loss in helix bundle stability upon beta-residue incorporation;
however, stability of the quaternary structure is not a simple function of
beta-residue content. We find that cyclically constrained beta-amino acid
residues can stabilize the folds of alpha/beta-peptide GCN4-pLI analogues and
restore quaternary structure formation to backbones that are predominantly
unfolded in the absence of cyclic residues. Our results show a surprising degree
of plasticity in terms of the backbone compositions that can manifest the
structural information encoded in a sequence of amino acid side chains. These
findings offer a framework for the design of nonnatural oligomers that mimic the
structural and functional properties of proteins.
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Figure 1.
Chemical structures and helical wheel diagrams of 1–9. (A)
Primary sequences of α-peptide 1 and α/β-peptides 2–9,
sorted according to α/β backbone pattern. Bold letters
indicate hydrophobic core residues in the GCN4-pLI sequence.
Colored circles indicate sequence positions occupied by
β-residues, cyan for β^3-residues and orange for cyclic
β-residues. (B) Helical wheel diagram of 1 with hydrophobic
core residues indicated. (C) Structures of an α-amino acid, a
β^3-amino acid, and the cyclic β-amino acids ACPC (X) and APC
(Z). (D) Helical wheel diagrams of the α/β residue patterns of
2–9 based on a heptad repeat. Each circle represents a residue
and is colored by residue type, yellow for α-residues, cyan for
β^3-residues, and orange for cyclic β-residues. Bold circles
indicate hydrophobic core positions.
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Figure 2.
Comparison of the GCN4-pLI side chain sequence on four
different backbone patterns. (A) Helix bundle quaternary
structures of each derivative with yellow and blue indicating
α- and β^3-residues, respectively. (B) Helical secondary
structures of each α/β-peptide 2–4 (red) compared with
that of α-peptide 1 (yellow); the overlays and accompanying
RMSD values are based on C[α] atoms in shared α-residues. The
coordinates for 1 (PDB: 1GCL) (21) and 2 (PDB: 2OXK) (14) were
obtained from previously published structures.
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