Metallo‐Foldamers with Backbone‐Coordinative Oxime Peptides: Control of Secondary Structures

Tashiro, Shohei; Matsuoka, Koji; Minoda, Ai; Shionoya, Mitsuhiko

doi:10.1002/anie.201206968

Cited by 22 publications

(17 citation statements)

References 77 publications

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“…First, it is located directly between two metal-binding residues (Cys 4 and Cys 7 ); small changes in local conformation could alter alignment of these side chains and their propensity to bind metal in the folded state. Second, analysis of the NMR structure of Sp1–3 indicates the backbone reversal is best classified as a “double turn,” 29 where a type-I turn encompassing Cys 4 –Cys 7 overlaps with a type-VIII turn encompassing Pro 5 –Pro 8 (Figure S2). The unnatural turn replacements employed in 2 and 3 are proven substitutions for canonical type-I and type-II turns; 30 however, they tend to promote mirror image type-I’ and II’ turn conformations that may be incompatible with the overlapping type-VIII turn directly following in Sp1–3 .…”

Section: Resultsmentioning

confidence: 99%

“…Peptides 5 and 6 were designed to examine whether the turn conformation might be the leading determinant against folding. Each incorporates a δ-residue as a dipeptide replacement in the center of the type-I turn encompassing Pro 5 –Pro 8 . Peptide 5 employs ornithine connected via its side chain to the preceding residue ( δ O ), a well-established turn inducer.…”

Section: Resultsmentioning

confidence: 99%

“…6 Despite this ubiquity in nature, examples of metal binding in foldamers represent only a small fraction of the many unnatural folded units reported to date. 7 Most examples have been based on oligomers with metal-coordinating backbones, 8 while some have shown metal binding is possible in designed oligomers with peptide-based backbones closer to those found in nature. 9 …”

Section: Introductionmentioning

confidence: 99%

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Heterogeneous-Backbone Foldamer Mimics of Zinc Finger Tertiary Structure

George

Horne

2017

J. Am. Chem. Soc.

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A variety of oligomeric backbones with compositions deviating from biomacromolecules can fold in defined ways. Termed “foldamers,” these agents have diverse potential applications. A number of protein-inspired secondary structures (e.g., helices, sheets) have been produced from unnatural backbones, yet examples of tertiary folds combining several secondary structural elements in a single entity are rare. One promising strategy to address this challenge is the systematic backbone alteration of natural protein sequences, through which a subset of the side chains is displayed on an unnatural building block to generate a heterogeneous backbone. A drawback to this approach is that substitution at more than one or two sites often comes at a significant energetic cost to fold stability. Here we report heterogeneous-backbone foldamers that mimic the zinc finger domain, a ubiquitous and biologically important metal-binding tertiary motif, and do so with a folded stability that is superior to the natural protein on which their design is based. A combination of UV-vis spectroscopy, isothermal titration calorimetry, and multidimensional NMR reveals that suitably designed oligomers with >20% modified backbones can form native-like tertiary folds with metal-binding environments identical to the prototype sequence (the third finger of specificity factor 1) and enhanced thermodynamic stability. These results expand the scope of heterogeneous-backbone foldamer design to a new tertiary structure class and show that judiciously applied backbone modification can be accompanied by improvement to fold stability.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Heterogeneous-Backbone Foldamer Mimics of Zinc Finger Tertiary Structure

George

Horne

2017

J. Am. Chem. Soc.

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“…As expected, the reverse reaction quantitatively proceeded by adding HBF 4 as an acid to the resulting solution (Figure 5c). 47 Thus, the combination of metals and acidbase balance is a promising tool to develop synthetic metallopeptides that would show rapid, dynamic structural conversion by solution components.…”

Section: ç Acid-base-responsive Metallopeptidesmentioning

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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“…[24][25][26][27][28][29] Ab initio metallo-protein design including second sphere control has also witnessed remarkable advances. [30][31][32][33][34][35] Because of their biological inspiration, metallofoldamers, [36][37][38][39][40][41][42] i.e. synthetic folded oligomers incorporating metal ions, may have potential for implementing second sphere interactions as they occur in proteins.…”

Section: Introductionmentioning

confidence: 99%