Detection and Analysis of Chimeric Tertiary Structures by Backbone Thioester Exchange: Packing of an α Helix against an α/β‐Peptide Helix

Price, Joshua L.; Hadley, Erik B.; Steinkruger, Jay D.; Gellman, Samuel H.

doi:10.1002/anie.200904714

Cited by 52 publications

(61 citation statements)

References 48 publications

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“…2 More recent work has sought to create unnatural backbones mimic target folds with increased intricacy, such as multi-helix quaternary assemblies, 3 multi-stranded sheets, 4 and unimolecular tertiary structures. 5 The design of such molecules remains a significant challenge, the magnitude of which scales with the complexity of the desired fold.…”

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: Introductionmentioning

confidence: 99%

“…More recent efforts have expanded to tertiary structure contexts, specifically a disulfide-cyclized helix-turn-helix motif derived from Staphylococcal protein A 13,15 and the α/β tertiary fold of the B1 domain of Streptococcal protein G (GB1). 4c,5d,16 …”

Section: Introductionmentioning

confidence: 99%

Heterogeneous-Backbone Foldamer Mimics of Zinc Finger Tertiary Structure

George

Horne

2017

J. Am. Chem. Soc.

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“…Early advances toward this goal included reports of bundled quaternary assemblies of foldameric helices 2 as well as related helix-turn-helix motifs. 3 While these examples represent important milestones, the fraction of known natural protein folding motifs successfully recreated in non-biological backbones remains very small. A significant limiting factor that has held back the field is the challenge of design.…”

Section: Introductionmentioning

confidence: 99%

Protein backbone engineering as a strategy to advance foldamers toward the frontier of protein-like tertiary structure

Reinert

Horne

2014

Org. Biomol. Chem.

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A variety of non-biological structural motifs have been incorporated into the backbone of natural protein sequences. In parallel work, diverse unnatural oligomers of de novo design (termed “foldamers”) have been developed that fold in defined ways. In this Perspective article, we survey foundational studies on protein backbone engineering, with a focus on alterations made in the context of complex tertiary folds. We go on to summarize recent work illustrating the potential promise of these methods to provide a general framework for the construction of foldamer mimics of protein tertiary structures.

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“…In more than two decades of work showing increasingly sophisticated structures from unnatural backbones, tertiary folds like those commonly found in proteins have proven difficult to recreate. Although significant progress has been made with helix-turn-helix targets, 3 these represent only a small fraction of the diverse array of folds found in nature. Reproducing a wider selection of natural protein structural motifs with unnatural oligomers is an important goal because it opens the door to reproducing the full repertoire of functions enabled by those folds.…”

Section: Introductionmentioning

confidence: 99%

Comparison of backbone modification in protein β-sheets by α→γ residue replacement and α-residue methylation

et al. 2014

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The mimicry of protein tertiary structure by oligomers with unnatural backbones is a significant contemporary research challenge. Among common elements of secondary structure found in natural proteins, sheets have proven the most difficult to address. Here, we report the systematic comparison of different strategies for peptide backbone modification in β-sheets with the goal of identifying the best method for replacing a multi-stranded sheet in a protein tertiary fold. The most effective sheet modifications examined lead to native-like tertiary folding behavior with thermodynamic fold stability comparable to the prototype protein on which the modified backbones are based.

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Detection and Analysis of Chimeric Tertiary Structures by Backbone Thioester Exchange: Packing of an α Helix against an α/β‐Peptide Helix

Cited by 52 publications

References 48 publications

Heterogeneous-Backbone Foldamer Mimics of Zinc Finger Tertiary Structure

Heterogeneous-Backbone Foldamer Mimics of Zinc Finger Tertiary Structure

Protein backbone engineering as a strategy to advance foldamers toward the frontier of protein-like tertiary structure

Comparison of backbone modification in protein β-sheets by α→γ residue replacement and α-residue methylation

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