Metallopeptide Design:  Tuning the Metal Cation Affinities with Unnatural Amino Acids and Peptide Secondary Structure

Cheng, Richard P.; Fisher, Stewart L.; Imperiali, Barbara

doi:10.1021/ja9619723

Cited by 108 publications

(95 citation statements)

References 31 publications

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“…However, due to the lower extinction coefficient for the metal-to-ligand charge transfer (MLCT) and d-d transitions, we are unable to rule out the possibility that formation of a 1:1 complex is followed by the formation of a 1.5:1 or 2:1 complex as observed previously for related small model compounds with glutathione (GS) in place of GCN4bd (bipyGS 2 and terpyGS 2 ). [27] The results summarised in Table 1 are in good agreement with previous reports for related polypyridyl Cu/Zn coordination, [41,42] displaying a higher affinity for Cu II than for Zn II . The binding constants reported for the Zn-bipy(GCN4bd) 2 and Cuterpy(GCN4bd) 2 complexes, are similar to those we previously reported for the analogous glutathione dimers, bipyGS 2 and terpyGS 2 .…”

Section: Uv-visible Cusupporting

confidence: 90%

“…[27,46,47] The bands shift to lower energy upon Zn II and Cu II complexation, allowing estimation of an apparent binding constant. [41] Aliquots of a stock solution of ZnCl 2 were titrated into a 5 mm solution of bipy(GCN4bd) 2 or terpy(GCN4bd) 2 in 20 mm phosphate buffer pH 7.4, up to 3 equivalent of ZnCl 2 . This resulted in the steady decrease in the absorbance at 299 (bipy-(GCN4bd) 2 ) and 298 nm (terpy(GCN4bd) 2 ), and an increase in the absorbance at 313 and 320 nm (bipy(GCN4bd) 2 ), and 328 and 341 nm (terpy(GCN4bd) 2 ; Figure 6).…”

Section: Uv-visible Cumentioning

confidence: 99%

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Metal‐Ion‐Regulated Miniature DNA‐Binding Proteins Based on GCN4 and Non‐native Regulation Sites

Oheix

Peacock

2014

Chemistry A European J

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The design of artificial peptide dimers containing polypyridine switching domains, for which metal-ion coordination is shown to regulate DNA binding, is reported. Short peptides, based on the basic domain of the GCN4 transcription factor (GCN4bd), dimerised with either 2,2'-bipyridine (bipy(GCN4bd) 2 ) or 2,2':6',2''-terpyridine (terpy(GCN4bd) 2 ) linker units, undergo a conformational rearrangement on Cu II and Zn II coordination. Depending on the linker substitution pattern, this is proposed to alter the relative alignment of the two peptide moieties, and in turn regulate DNA binding. Circular dichroism and UV-visible spectroscopy reveal that Cu II and Zn II coordination promotes binding to DNA containing the CRE target site, but to a differing and opposite degree for the two linkers, and that the metal-ion affinity for terpy(GCN4bd) 2 is enhanced in the presence of CRE DNA. Binding to DNA containing the shorter AP1 target site, which lacks a single nucleobase pair compared to CRE, as well as half-CRE, which contains only half of the CRE target site, was also investigated. Cu II and Zn II coordination to terpy(GCN4bd) 2 promotes binding to AP1 DNA, and to a lesser extent half-CRE DNA. Whereas, bipy(GCN4bd) 2 , for which interpeptide distances are largely independent of metal-ion coordination and less suitable for binding to these shorter sites, displays allosteric ineffective behaviour in these cases. These findings for the first time demonstrate that biomolecular recognition, and specifically sequence-selective DNA binding, can be controlled by metal-ion coordination to designed switching units, non-native regulation sites, in artificial biomolecules. We believe that in the future these could find a wide range of applications in biotechnology.

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Section: Uv-visible Cusupporting

confidence: 90%

Section: Uv-visible Cumentioning

confidence: 99%

Metal‐Ion‐Regulated Miniature DNA‐Binding Proteins Based on GCN4 and Non‐native Regulation Sites

Oheix

Peacock

2014

Chemistry A European J

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“…41 Imperiali et al successfully incorporated synthetic amino acids bearing a bipyridine or phenanthrolinependant side chain 44 into peptides so that the metal coordinating side chains bind to Zn II ions to stabilize ¢-hairpin conformation (Figure 4d). 42 Another challenge is to construct metallopeptides adopting a more complicated secondary or ternary structure through metal coordination. Ishida et al reported a synthetic peptide, H-GGA-bpy-FGPGGA-bpy-FGPGGA-bpy-FGG-NH 2 , 25 containing three bipyridine-type amino acids in the main chain along with L-Pro-Gly sequences which readily form a turn structure.…”

Section: ç Metal-mediated Stabilization Of Sheet Structuresmentioning

confidence: 99%

Stimuli-responsive Synthetic Metallopeptides

Tashiro

Shionoya

2013

Chemistry Letters

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Inspired by vital roles of metal ions as structure-stabilizing and regulating factors in biological systems, a great number of synthetic metallopeptides have been developed. This review focuses on metal-mediated stabilization and stimuli-responsive regulation of their secondary and higher-order structures by taking advantage of the characteristics of metal ions such as Lewis acidity, ligand-exchange ability, and redox properties. Ç IntroductionIn metal-including biomolecules such as metalloproteins or enzymes in living systems, metal ions play vital roles in molecular recognition, catalytic reaction, transportation, electron transfer, and structure stabilization or regulation.1 Focusing on a few examples of metal-mediated formation of higher-order structures of proteins, a typical example is zinc-finger proteins, which are composed of multiple finger units containing one Zn II ion bound by four coordinating side chains of His and/or Cys residues. The Zn II ions are well-known to stabilize the whole ternary structures and essential for DNA binding.2 In other cases, several metal ions such as Zn II , Cu II , and Fe III are considered a trigger for protein aggregations through interactions with some protein domains as seen in several brain disorders such as Alzheimer's disease and Parkinson's disease, 3 in which metal ions serve as inducers of protein folding or aggregation. On the other hand, metal ions in some proteins can regulate their higherorder structures through response to several stimuli, and the structural transformation is involved in protein functions. Hemoglobin is a typical example of such proteins, 4 that is a tetrameric protein in which O 2 trapping at the Fe II center of one heme unit induces the whole conformation change (T ¼ R transition) to achieve cooperative binding of molecular oxygens. One way to understand and further utilize such protein natures is a synthetic approach to stimuli-responsive mechanisms inspired by natural metalloproteins.For this purpose, design-based incorporation of metal binding sites into peptide structures has been extensively conducted. Synthetic peptides developed so far can be categorized as two types: (i) natural ¡-peptides possessing an optional sequence that can bind to metal ions through their coordinating functionalities of the residues or (ii) unnatural peptides containing synthetic amino acid residues whose side and/or main chains bind to metal ions. So far, many types of synthetic peptides have been reported based on both strategies, and the stabilization of secondary and higher-order structures of their metallopeptides has been demonstrated. Moreover, the metalmediated regulation of peptide structures has been recently studied based on the characteristics of metal ions such as Lewis acidity, ligand-exchange ability, and redox properties (Figure 1). This review describes the design outline of metallopeptides and then metal-mediated stabilization of ¡-helix and ¢-sheet structures taking a few basic examples of stimuli-responsive folding. The structu...

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“…Finally, the genetic incorporation of BpyAla and other metal-chelating amino acids into proteins provides a novel approach towards the de novo engineering of metalloproteins with a range of novel structures and functions, including oligomeric polypeptides (e.g., helical bundles [17][18][19] ) or proteins with redox-active, radioactive, or fluorescent metal ion complexes. [20][21][22][23][24] …”

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confidence: 99%

A Genetically Encoded Bidentate, Metal‐Binding Amino Acid

2007

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A two‐ring binder: To facilitate the design of metalloproteins, the bidentate, metal‐binding amino acid bipyridylalanine (BpyAla) was genetically encoded in E. coli in response to the amber nonsense codon with high fidelity and yield. The incorporation of BpyAla requires a BpyAla‐specific aminoacyl‐tRNA synthetase, which was evolved in a stepwise fashion. The structural basis of selective recognition of BpyAla by this synthetase was also determined.

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Metallopeptide Design: Tuning the Metal Cation Affinities with Unnatural Amino Acids and Peptide Secondary Structure

Cited by 108 publications

References 31 publications

Metal‐Ion‐Regulated Miniature DNA‐Binding Proteins Based on GCN4 and Non‐native Regulation Sites

Metal‐Ion‐Regulated Miniature DNA‐Binding Proteins Based on GCN4 and Non‐native Regulation Sites

Stimuli-responsive Synthetic Metallopeptides

A Genetically Encoded Bidentate, Metal‐Binding Amino Acid

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