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metal-binding coordination is formed that mimics the Zn
2þ
finger motif [250]. A shorter
Zn-binding peptide of 27 amino acids was suspected to form a helical bundle structure in
the absence of Zn
2þ
, whereas it forms a folded helix-b-sheet structure triggered by Zn
2þ
binding [251] which represents a typical example of metal switching in peptide folding.
A number of peptides are synthesized with built-in metal-binding motif(s) which
include nonamino acid ligands. An amphiphilic peptide with a 2,2
0
-bipyridine (bpy) group
attached to the N-terminus via a 4-carboxyl group, for example, (4-carboxyl-bpy)-Gly-
Glu-
Leu-
Ala-Gln-Lys-
Leu
-Glu-Gln-Ala-
Leu
-Gln-Lys-
Leu
-Ala-NH
2
,isexpectedto
have the four Leu side chains facing to the same side once a helical structure is formed
[252]. In the presence of Ni
2þ
,Co
2þ
,orRu
2þ
, the peptide assembles into a 45-residue
three-bundled coiled-coil structure that is confirmed by mass spectrometry of the inert
Ru
2þ
-bound three bundle with
m
/
z
5563 [253]. The CD spectra of the metallopeptide
reveal 80% a-helicity in 150 mM NaCl solution and the formation of one diastereomer
with a L-isomeric tris-bipyridyl-M
2þ
center and a left-handed coiled-coil structure. The
introduction of an additional sequence of Ala-Ala-His-Tyr to the C-terminus of the above
peptide affords another three-bundled assembly in the presence of Ru
2þ
with an addi-
tional tri-His binding site from the three bundles for Cu
2þ
binding [254]. The use of a
N-terminal monodentate metal-binding site in a peptide affords nicotinyl-g-aminobu-
tylic-Gly-Leu-Ala-Gln-Lys-Leu-Leu-Glu-Ala-Leu-Gln-Lys-Ala-Leu-Ala which binds
Ru
2þ
in a 4 : 1 ratio to assemble into an inert four-bundled coiled-coil structure, demon-
strated by means of atomic absorption spectroscopy and electrospray mass spectrometry
[255]. A few 3,3
0
-peptidyl derivatives of 2,2
0
-bipyridine show an extended configuration
which fold to render b-sheet structures upon Cu
2þ
binding based on CD spectra [256],
representing another example of metal-triggered peptide folding.
¼
1.4 Conclusion and Perspectives
The biological activities of proteins and peptides rely on the proper folding of their pep-
tide chains. In some diseased stages, misfolded natural peptide chains can form organized
tertiary and higher-order structures which may be further triggered by metal binding, as
found in amyotrophic lateral sclerosis due to Cu,Zn-superoxide dismutase, Alzheimer's
disease due to b-amyloid, and prion diseases due to the prion proteins discussed above,
reflecting the great conformational flexibility of peptide chains. Metal ions can also medi-
ate the assembly of synthetic/designed peptides to form nanoscale spheres and fibrils
[257] and microflorettes [258]. In some other instances, the binding of different metal
ions to a peptide chain may afford conformational changes to a certain extent and afford
different bioactivities, as in the case of the various metal-dependent activities of the
dinuclear aminopeptidase from
Streptomyces
discussed above. The Ni
2þ
-andFe
2þ
-
substituted forms of acireductone dioxygenase serve as another example of metallopro-
tein foldamers with different enzymatic reactions [259]. Future structural studies about
substrate binding modes in the ES complexes and the transition state are expected to pro-
vide further insight into the mechanisms for the different catalyses by the different metal
forms of each individual protein. Proteins and peptides have chiral-specific properties as
their amino acids building blocks are chiral and only the
L
-form is incorporated into living
systems. Consequently, a totally synthesized
Desuljiwibrio
iron-sulfur protein rubredoxin
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