Exploiting Polypeptide Motifs for the Design of Selective Cu(II) Ion Chemosensors

Torrado, Alicia; Walkup, Grant K.; Imperiali, Barbara

doi:10.1021/ja973357k

Cited by 319 publications

(164 citation statements)

References 11 publications

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“…97,98 However, complete control of a cofactor's environment might be best effected through the de novo design [99][100][101][102] of proteins whose active sites are defined by the favorable free energy of folding of the polypeptide chain. There has also been much progress made in the de novo design of proteins that bind metalloporphyrins [92][93][94][95][103][104][105] and Zn-(II). 20,106 The structures of some simple porphyrin peptide complexes have been solved by NMR.…”

Section: From Structure To Function: Design Of Metalloproteinsmentioning

confidence: 99%

De NovoDesign of Helical Bundles as Models for Understanding Protein Folding and Function

et al. 2000

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De novo protein design has proven to be a powerful tool for understanding protein folding, structure, and function. In this Account, we highlight aspects of our research on the design of dimeric, four-helix bundles. Dimeric, four-helix bundles are found throughout nature, and the history of their design in our laboratory illustrates our hierarchic approach to protein design. This approach has been successfully applied to create a completely native-like protein. Structural and mutational analysis allowed us to explore the determinants of native protein structure. These determinants were then applied to the design of a dinuclear metal-binding protein that can now serve as a model for this important class of proteins.Protein folding is an important and multifaceted scientific problem. 1-8 One facet of this problem involves the prediction of three-dimensional structure from amino acid sequence, an endeavor the importance of which has been highlighted by the recent release of gene sequences of many whole organisms. As the size of the protein structural database expands, it will be increasingly possible to assign amino acid sequences to a given structural family on the basis of the homology of their sequences with proteins of known structure. Another facet of the folding problem is the delineation of the kinetic mechanism by which an unfolded protein chain undergoes the transition from a random coil with an astronomical number of configurations to a uniquely folded structure. A final facet of the protein folding problem is to understand, at the atomic level, the detailed physicochemical features that kinetically and thermodynamically direct the formation of an unique, cooperatively folded, native structure. This latter endeavor is particularly important as it lays the groundwork for the design of novel inhibitors of natural proteins as well as the construction of novel proteins and related biopolymers not found in nature.De novo protein design is an approach to the protein folding problem that critically tests our understanding of all these facets of this problem. 9,10 This method involves the design of a sequence that is intended to fold into a predetermined three-dimensional structure without the sequence being patterned after any natural protein. Through an iterative process of design and rigorous characterization, the principles governing protein folding and function can be evaluated. Thus, "failures" highlight gaps in our understanding, whereas "successes" confirm the principles used in the design and often provide simple model systems to further

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Section: From Structure To Function: Design Of Metalloproteinsmentioning

confidence: 99%

De NovoDesign of Helical Bundles as Models for Understanding Protein Folding and Function

et al. 2000

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“…Automated methods have been developed recently for engineering such ion-binding sites (15,16), and it has been possible to build a number of structural as well as redox-active metal ion-binding sites within several different proteins (17)(18)(19)(20). Another successful approach has been to design small flexible peptides that are able to fold around metal sites such as Cu(II)-binding motifs (21)(22)(23)(24) and small peptides that assemble into Fe 4 S 4 clusters (25,26).…”

mentioning

confidence: 99%

Retrostructural analysis of metalloproteins: Application to the design of a minimal model for diiron proteins

Lombardi

Summa

Geremia

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

233

279

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De novo protein design provides an attractive approach for the construction of models to probe the features required for function of complex metalloproteins. The metal-binding sites of many metalloproteins lie between multiple elements of secondary structure, inviting a retrostructural approach to constructing minimal models of their active sites. The backbone geometries comprising the metal-binding sites of zinc fingers, diiron proteins, and rubredoxins may be described to within approximately 1 Å rms deviation by using a simple geometric model with only six adjustable parameters. These geometric models provide excellent starting points for the design of metalloproteins, as illustrated in the construction of Due Ferro 1 (DF1), a minimal model for the GluXxx-Xxx-His class of dinuclear metalloproteins. This protein was synthesized and structurally characterized as the di-Zn(II) complex by x-ray crystallography, by using data that extend to 2.5 Å. This four-helix bundle protein is comprised of two noncovalently associated helix-loop-helix motifs. The dinuclear center is formed by two bridging Glu and two chelating Glu side chains, as well as two monodentate His ligands. The primary ligands are mostly buried in the protein interior, and their geometries are stabilized by a network of hydrogen bonds to second-shell ligands. In particular, a Tyr residue forms a hydrogen bond to a chelating Glu ligand, similar to a motif found in the diiron-containing R2 subunit of Escherichia coli ribonucleotide reductase and the ferritins. DF1 also binds cobalt and iron ions and should provide an attractive model for a variety of diiron proteins that use oxygen for processes including iron storage, radical formation, and hydrocarbon oxidation. P roteins use a limited repertoire of metal ion cofactors to help catalyze a multitude of reactions. For example, diiron sites (1-4) mediate reversible oxygen binding in hemerythrins, whereas they function as hydrolytic centers in phosphatases. Structurally similar diiron sites also mediate a number of oxygendependent oxidative processes. Ferritins serve as ferroxidases, while other diiron proteins catalyze hydroxylation, epoxidation, and desaturation reactions. Further, a diiron site in Escherichia coli ribonucleotide reductase is responsible for the formation of a Tyr radical. How do the structures of these proteins tune the chemical properties of a common diiron center to obtain such a diversity of highly specific catalysts? This question is being addressed through the study of the natural proteins as well as the study of small-molecule diiron complexes (1-4). Although impressive progress has been made on both fronts, these approaches have inherent limitations. The study of large proteins is hampered by their extreme complexity, and it is difficult to synthesize small-molecule models capable of simultaneously binding diiron, oxygen, and various substrates. Recently, we and others have sought a molecular middle ground between these two extremes through the design of small proteins and peptid...

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“…3 Számos publikáció igazolja a fenti szerkezeti csoportokba sorolható fluorofór-jelzett peptidek alkalmazhatóságát fémionok érzékelésére. Mûködési elvük szerint "TURN ON" választ adó CHEF (chelation-enhanced fluorescence), [14][15][16][17] "TURN OFF" jellegû CHEQ (chelation-enhanced quenching), 17,18 illetve FRET típusú szenzorokat is vizsgáltak. 19,20 A szenzorikai alkalmazhatóság szempontjából ideális "TURN ON" választ, de a "TURN OFF" effektust is a fluorofór gerjesztett állapotának HOMO 21 Mindenképpen meg kell jegyezni, hogy CHEF vagy CHEQ hatást más mechanizmusok is eredményezhetnek.…”

Section: Bevezetésunclassified

“…A fémionokkal képzõdõ komplexek oldatbeli speciációjának feltérképezése azonban szinte mindig hiányzik ezekbõl a munkákból, noha ennek esszenciális jelentõsége lenne a vegyületek alkalmazhatósági körülményeinek (pH-és koncentráció-tartomány, fémion-ligandum arány) megállapítása, vagy a molekulák továbbfejlesztése szempontjából. Ugyancsak ritka, hogy az érzékelõ rendszereket immobilizált formában is vizsgálnák, 18,22 ami viszont a szenzorikai alkalmazásuk szempontjából lenne kulcsfontosságú.…”

Section: Bevezetésunclassified

Metalloproteinek fémkötőhelyein alapuló oligopeptidek, mint potenciális toxikus fémion érzékelők

Szekeres¹,

Szunyogh²,

Galbács³

et al. 2017

MKF

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Exploiting Polypeptide Motifs for the Design of Selective Cu(II) Ion Chemosensors

Cited by 319 publications

References 11 publications

De NovoDesign of Helical Bundles as Models for Understanding Protein Folding and Function

De NovoDesign of Helical Bundles as Models for Understanding Protein Folding and Function

Retrostructural analysis of metalloproteins: Application to the design of a minimal model for diiron proteins

Metalloproteinek fémkötőhelyein alapuló oligopeptidek, mint potenciális toxikus fémion érzékelők

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