The KNOTTIN database

Folding may imply complex equilibrium and disulfide reshuffling

  •  Although disulfide bridges are responsible for the high stability of Knottins, they also render the folding process more complex, especially in chemical synthesis.
  • Since Knottins are considered as interesting leads in drug design, it is essential to understand the basic principles that govern the folding process. This would help in rational knottin-based drug-design studies.
  • Main historical and recent efforts along this way are outlined below.
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Squash inhibitors

alpha-Amylase Inhibitor

Carboxypeptidase inhibitor

Conotoxins

Spider toxins

Cyclotides

General review on the oxidative folding of small disulfide-rich proteins are available [Arolas et al, 2006; Craik 2010].

Spider toxins

Mature GsMTx4 is able to fold properly

Oxidative folding of mature GsMTx4 yields the correct folded peptide [Ostrow et al., 2003]. In the absence of GSSG/GSSH, oxidation of the linear precursor yields a mixture of misfolded forms with incorrectly paired disulfides. After addition of GSSG/GSSH, the mixture shifted to the correctly folded state. The propeptides are unnecessary for proper folding. These results are consistent with previous results on ω-conotoxin MVIIA.