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Chemical ligation

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Title: Chemical ligation  
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Subject: Ligation, Chemical synthesis, Isopenicillin N synthase, CD47, Intein
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Chemical ligation

Chemical ligation is a set of techniques used for creating long peptide or protein chains. It is the second step of a convergent approach. First, smaller peptides containing 30-50 amino acids are prepared by conventional chemical peptide synthesis. Then, they are completely deprotected. Chemical ligation is the technique of coupling these peptides by chemoselective reaction to give a unique reaction product, usually in aqueous solution. With several coupling steps, proteins of up to 200-300 amino acids can be produced.


  • Methods of chemical ligation 1
    • Expressed protein ligation 1.1
    • Staudinger ligation 1.2
  • References 2
  • External links 3

Methods of chemical ligation

There are various techniques described in literature. The most practical and robust method for the chemoselective reaction of unprotected peptides is amide bond.

Native chemical ligation relies on the presence of a cysteine residue at the ligation site. Methods using removable auxiliary groups can in some instances extend the use of native chemical ligation to non-cysteine residues, as can the use of desulfurization subsequent to the ligation (e.g. converting a Cys to an Ala).

Expressed protein ligation

By exploiting naturally occurring inteins it is possible to prepare a recombinant polypeptide C-terminal thioester. This enables the use of large recombinant protein-derived thioesters in native chemical ligation. The recombinant thioester can be ligated to a synthetic peptide bearing an N-terminal cysteine. Native chemical ligation of this kind using recombinant C-terminal thioesters is known as expressed protein ligation. Recombinant expression can also be used to give a Cys-polypeptide for use in native chemical ligation.

Staudinger ligation

The Staudinger ligation, first reported in 2000, in principle enables the ligation of peptide segments independent of the terminal amino acids. The method is based on the Staudinger reaction. The Staudinger ligation continues to be developed and has not yet found widespread use.


Schnölzer M, Kent SB. 1992, "Constructing proteins by dovetailing unprotected synthetic peptides: backbone-engineered HIV protease." Science. 256:221-5

Dawson PE, Muir TW, Clark-Lewis I, Kent SB. 1994, "Synthesis of proteins by native chemical ligation." Science. 266:776-9.

Muir TW. 2003, "Semisynthesis of proteins by expressed protein ligation." Annu Rev Biochem. 72:249-89.

Nilsson BL, Soellner MB, Raines RT. 2005, "Chemical Synthesis of Proteins." Annu. Rev. Biophys. Biomol. Struct. 34:91-118

Bang D, Pentelute BL, Kent SB. 2006, "Kinetically controlled ligation for the convergent chemical synthesis of proteins." Angew Chem Int Ed Engl. 45:3985-8.

Kent SB. 2009, "Total chemical synthesis of proteins." Chem.Soc.Rev. 38, 338-351. doi:10.1039/b700141j.

External links

  • Instant insight outlining chemical ligation from the Royal Society of Chemistry
  • Chemical Ligation Aldrich ChemFiles 2008 Vol. 8, No. 1, giving an overview on modern Chemical Ligation methods and literature.
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