Synthesis of a bicyclic dipeptide with the shape of β-turn central part

Nagai, Ukon; Sato, Kazuki

doi:10.1016/s0040-4039(00)89169-8

Cited by 152 publications

(71 citation statements)

References 9 publications

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“…1). ␤-Turn mimics 1, 4, and 6 were designed to replace the i ϩ 1 and i ϩ 2 residues of a type IIЈ ␤-turn and were anticipated to match the right-handed twist of Pin WW (21,25). Compound 1 has reduced conformational freedom relative to 4 and 6.…”

Section: Resultsmentioning

confidence: 99%

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Evaluating β-turn mimics as β-sheet folding nucleators

Fuller

Liu

et al. 2009

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

100

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␤-Turns are common conformations that enable proteins to adopt globular structures, and their formation is often rate limiting for folding. ␤-Turn mimics, molecules that replace the i ؉ 1 and i ؉ 2 amino acid residues of a ␤-turn, are envisioned to act as folding nucleators by preorganizing the pendant polypeptide chains, thereby lowering the activation barrier for ␤-sheet formation. However, the crucial kinetic experiments to demonstrate that ␤-turn mimics can act as strong nucleators in the context of a cooperatively folding protein have not been reported. We have incorporated 6 ␤-turn mimics simulating varied ␤-turn types in place of 2 residues in an engineered ␤-turn 1 or ␤-bulge turn 1 of the Pin 1 WW domain, a three-stranded ␤-sheet protein. We present 2 lines of kinetic evidence that the inclusion of ␤-turn mimics alters ␤-sheet folding rates, enabling us to classify ␤-turn mimics into 3 categories: those that are weak nucleators but permit Pin WW folding, native-like nucleators, and strong nucleators. Strong nucleators accelerate folding relative to WW domains incorporating all ␣-amino acid sequences. A solution NMR structure reveals that the native Pin WW ␤-sheet structure is retained upon incorporating a strong E-olefin nucleator. These ␤-turn mimics can now be used to interrogate protein folding transition state structures and the 2 kinetic analyses presented can be used to assess the nucleation capacity of other ␤-turn mimics.beta-sheet nucleator ͉ kinetic assessment of turn mimics ͉ Pin WW domain ͉ protein folding

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Section: Resultsmentioning

confidence: 99%

“…1) (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). For the purpose of this paper, ␤-turn mimics are defined as molecules that replace the i ϩ 1 and i ϩ 2 amino acid residues of a ␤-turn.…”

mentioning

confidence: 99%

Evaluating β-turn mimics as β-sheet folding nucleators

Fuller

Liu

et al. 2009

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

100

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“…With chemical synthesis, virtually any conceivable covalent modification can be introduced at will anywhere in the protein molecule. An early example of the utility of this approach was the total chemical synthesis of (BTD) HIV-1 protease (87), a protein in which the Gly-Gly sequence found in a β-turn in the native protein (20) was replaced by the sterically constrained bicyclic compound BTD, a rigid mimetic of type II β-turn geometry (88). The resulting enzyme showed full activity and a significantly enhanced thermostability (87).…”

Section: Precise Covalent Modificationmentioning

confidence: 99%

Synthesis of Native Proteins by Chemical Ligation

Dawson

Kent²

2000

Annu. Rev. Biochem.

1,587

1,526

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Key Words chemical protein synthesis, thioester, protein, peptide, solid phase synthesis, polymer-supported synthesis, protein engineering s Abstract In just a few short years, the chemical ligation of unprotected peptide segments in aqueous solution has established itself as the most practical method for the total synthesis of native proteins. A wide range of proteins has been prepared. These synthetic molecules have led to the elucidation of gene function, to the discovery of novel biology, and to the determination of new three-dimensional protein structures by both NMR and X-ray crystallography. The facile access to novel analogs provided by chemical protein synthesis has led to original insights into the molecular basis of protein function in a number of systems. Chemical protein synthesis has also enabled the systematic development of proteins with enhanced potency and specificity as candidate therapeutic agents.

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“…BTD (bicyclic turn dipeptide: (3S,6S,9R)-2-oxo-3-t-butyloxycarboxylamino-7-thia-l-aza-bicyclo[4.3.0]nonane-9-carboxylic acid) (Fig. l), a rigid bicyclic &turn analog mimicking a type 11' P-turn (Nagai & Sato, 1985;Osano et al, 1989), was incorporated into the polypeptide in place of residues GlyI6-GlyI7 in the HIV-1 protease monomer sequence (Fig. 2).…”

Section: Protein Synthesismentioning

confidence: 99%

Structural engineering of the HIV‐1 protease molecule with a β‐turn mimic of fixed geometry

1993

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An important goal in the de novo design of enzymes is the control of molecular geometry. To this end, an analog of the protease from human immunodeficiency virus 1 (HIV-1 protease) was prepared by total chemical synthesis, containing a constrained, nonpeptidic type 11' 0-turn mimic of predetermined three-dimensional structure.The mimic &turn replaced residues GlyI6,l7 in each subunit of the homodimeric molecule. These residues constitute the central amino acids of two symmetry-related type I' 0-turns in the native, unliganded enzyme. The 0-turn mimic-containing enzyme analog was fully active, possessed the same substrate specificity as the GlyI67l7-containing enzyme, and showed enhanced resistance to thermal inactivation. These results indicate that the precise geometry of the @turn at residues 15-18 in each subunit is not critical for activity, and that replacement of the native sequence with a rigid 0-turn mimic can lead to enhanced protein stability. Finally, the successful incorporation of a fixed element of secondary structure illustrates the potential of a "molecular kit set" approach to protein design and synthesis.

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Synthesis of a bicyclic dipeptide with the shape of β-turn central part

Cited by 152 publications

References 9 publications

Evaluating β-turn mimics as β-sheet folding nucleators

Evaluating β-turn mimics as β-sheet folding nucleators

Synthesis of Native Proteins by Chemical Ligation

Structural engineering of the HIV‐1 protease molecule with a β‐turn mimic of fixed geometry

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