Cyclic Peptides Bearing a Side‐Chain Tail: A Tool to Model the Structure and Reactivity of Protein Zinc Sites

Sénèque, Olivier; Bourlès, Emilie; Lebrun, Vincent; Bonnet, Estelle; Dumy, Pascal; Latour, Jean‐Marc

doi:10.1002/ange.200800677

Cited by 7 publications

(22 citation statements)

References 17 publications

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“…The UV/Vis titrations display an increase of the extinction coefficient Δ ε of 22900 and 24900 M −1 cm −1 at 209 nm for L4 and L5, respectively; this is in good agreement with the formation of Zn(Cys) 4 complexes 55. 57, 63 However, contrary to L HSP , these titrations do not show a clean plateau for the UV/Vis and CD signals after 1.0 equivalent of Zn 2+ , suggesting the formation of a complex of different stoichiometry in the presence of excess Zn 2+ . Nevertheless, the 1:1 complex seems to remain the major species.…”

Section: Resultssupporting

confidence: 75%

“…54 Noteworthy, the crystal structure of Hsp33 shows a hydrogen bond between the hydroxyl group of Tyr270, located in the β‐hairpin, and Cys233 Sγ, which is located in the coil 54. 57, 58 To use the smallest cycle as possible but also to incorporate this tyrosine, a 12 amino acid cycle comprising 10 amino acids of the β‐hairpin (from V 261 to Y 270 ) plus the D ‐Pro‐ L ‐Pro template was designed. The fold of L HSP around Zn 2+ is very close to that of Hsp33, the β‐hairpin is correctly folded and the TyrOH ⋅⋅⋅ S hydrogen bond is present (Figure 4 B).…”

Section: Resultsmentioning

confidence: 99%

“…The dashed box highlights the linker. B) Superimposition of the NMR solution structure of the Zn ⋅ L HSP complex57 (green) and the crystallographic structure of the ZF site of Thermotoga maritima Hsp33 (blue, pdb 1VQ0) 54…”

Section: Resultsmentioning

confidence: 99%

“…(Figure 1 C). The former, L TC ,55 was designed after the treble‐clef ZF site of the Bacillus subtilis peroxide sensor PerR52, 56 and the latter, L HSP ,57 after the ZF site of Hsp33 58. 59 These proteins were chosen because the involvement of their ZF site in H 2 O 2 sensing was under discussion when we started this project.…”

Section: Introductionmentioning

confidence: 99%

“…57, 63 Compared to the native ZF sites, these model complexes successfully reproduce 1) the peptide fold around zinc, 2) the relative orientations of the cysteine side chains, and 3) the hydrogen‐bond network involving the coordinating sulfurs 55. 57 In this article we will discuss some factors (amino acid composition, length of the cycle and of the tail) that might influence the folding of CPLT‐based ZF models to assess what is important for the successful design of structurally relevant ZF models. Based on this, we will propose a CPLT‐based model for the zinc‐ribbon ZFs and compare it to a linear model peptide of identical sequence.…”

Section: Introductionmentioning

confidence: 99%

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On the Design of Zinc‐Finger Models with Cyclic Peptides Bearing a Linear Tail

Jacques

Mettra

Lebrun

et al. 2013

Chemistry A European J

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Cyclic peptides with a linear tail (CPLT) have been successfully used to model two zinc fingers (ZFs) adopting the treble-clef- and loosened zinc-ribbon folds. In this article, we examine the factors that may influence the design of such ZF models: mutations in the sequence, size of the cycle, and size of the tail. For this purpose, several peptides derived from the CPLT-based models of the treble-clef- and loosened zinc-ribbon ZF were synthesized and studied. CPLT-based models appear to be robust toward mutations, accommodate various cycle sizes, and are sensible to the size of the linking region of the tail located between the cycle and the coordinating amino acids. Based on these criteria, we describe the design of a new CPLT-based model for the zinc-ribbon ZFs, LZR , and compare it to a linear analogue, LZR(lin) . The model complex Zn⋅LZR is able to fold correctly around the metal ion contrary to Zn⋅LZR(lin) , suggesting that CPLT-based models are more likely to yield structurally meaningful models of ZF sites than linear peptide models. Finally, we draw some rules that could allow the design of new CPLT-based metallopeptides with a controlled fold.

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Section: Resultssupporting

confidence: 75%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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On the Design of Zinc‐Finger Models with Cyclic Peptides Bearing a Linear Tail

Jacques

Mettra

Lebrun

et al. 2013

Chemistry A European J

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Thermodynamic Stability Versus Kinetic Lability of ZnS₄ Core

Picot

Ohanessian

Frison

2010

Chemistry An Asian Journal

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Density Functional Theory and post-Hartree Fock calculations reveal an unusual energy profile for Zn-S and Zn-N bond dissociation reactions in several [Zn(SR)(4)](2-) and [Zn(Im)(SR)(3)](-) complexes. The Zn-S bond dissociation in tetrathiolate dianions, which is highly exothermic in the gas phase, proceeds through a late transition state which can be rationalized on the basis of an avoided crossing resulting from Coulomb repulsion between the anionic fragments and ligand-to-metal charge-transfer in the [Zn(SR)(4)](2-) complexes. When solvation models for water, DMSO, or acetonitrile are included, some complexes become stable while others are metastable, so this constitutes the first theoretical model which is in full agreement with the experimental data for various [Zn(SR)(4)](2-), [Zn(SR)(3)](-), and [Zn(Im)(SR)(3)](-) complexes. The analysis given here indicates that the Zn(Cys)(4) and Zn(His)(Cys)(3) cores of numerous proteins are metastable with respect to Zn-S and Zn-N bond dissociation, respectively. This is consistent with the kinetic lability at the zinc-centers and illustrates that in nature, thermodynamic stability is imparted upon the zinc cores by the protein environment.

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Cooperative Metal Binding and Helical Folding in Model Peptides of Treble‐Clef Zinc Fingers

Sénèque

Bonnet

Joumas

et al. 2009

Chemistry A European J

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Two peptides, L(TC) and L(TC)(T) have been synthesised to model the treble-clef zinc fingers encountered in many Zn(Cys)(4)-site-containing proteins. Both are cyclic peptides with a linear tail grafted on a glutamate side chain of the cycle. They differ by the length of this tail, which lacks five amino acids in L(TC)(T) compared to L(TC). Both peptides bind Zn(2+) and Co(2+) in 1:1 metal/peptide ratio and the structure of these complexes have been characterised by NMR, UV/Vis and CD spectroscopy. Both peptides fold the same way around the metal ion and they fully reproduce the classical fold of treble-clef zinc fingers and display an extended hydrogen-bond network around the coordinating sulfur atoms. The structures of the ML(TC) complexes reveal that the linear tail forms a short two-turn alpha-helix, present in the metallated form only. The formation of this helix constitutes a rare example of metal-induced folding. The second turn of this helix is composed of the five amino acids that are absent in L(TC)(T). The study of the pH-dependence of the Zn(2+) binding constants shows that the metal ion is bound by four cysteinates above pH 5.2 and the binding constants are the highest reported so far. Interestingly, the binding constant of Zn x L(TC) is about tenfold higher than that of Zn x L(TC)(T). This difference clearly indicates that the helix, present in Zn x L(TC) only, stabilises the Zn(2+) complex by about 1.2 kcal mol(-1). The origin of this stabilisation is ascribed to an electrostatic interaction between the [ZnS(4)](2-) centre and the helix. This reveals a cooperative effect: zinc binding allows the folding of the tail into a helix which, in turn, strengthens the zinc complex.

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Cyclic Peptides Bearing a Side‐Chain Tail: A Tool to Model the Structure and Reactivity of Protein Zinc Sites

Abstract: A near‐perfect model: The design of short peptides with cyclic and linear components allows mimicking of the structure and reactivity of protein tetracysteinate zinc sites, as illustrated by the superposition of the Zn(Cys)4 site of Hsp33 (blue) and its 20 amino acid model (green).

Cited by 7 publications

References 17 publications

On the Design of Zinc‐Finger Models with Cyclic Peptides Bearing a Linear Tail

On the Design of Zinc‐Finger Models with Cyclic Peptides Bearing a Linear Tail

Thermodynamic Stability Versus Kinetic Lability of ZnS₄ Core

Cooperative Metal Binding and Helical Folding in Model Peptides of Treble‐Clef Zinc Fingers

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Cyclic Peptides Bearing a Side‐Chain Tail: A Tool to Model the Structure and Reactivity of Protein Zinc Sites

Abstract: A near‐perfect model: The design of short peptides with cyclic and linear components allows mimicking of the structure and reactivity of protein tetracysteinate zinc sites, as illustrated by the superposition of the Zn(Cys)4 site of Hsp33 (blue) and its 20 amino acid model (green).

Cited by 7 publications

References 17 publications

On the Design of Zinc‐Finger Models with Cyclic Peptides Bearing a Linear Tail

On the Design of Zinc‐Finger Models with Cyclic Peptides Bearing a Linear Tail

Thermodynamic Stability Versus Kinetic Lability of ZnS4 Core

Cooperative Metal Binding and Helical Folding in Model Peptides of Treble‐Clef Zinc Fingers

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Product

Resources

About

Thermodynamic Stability Versus Kinetic Lability of ZnS₄ Core