Inhibitor cystine knot
An inhibitor cystine knot (ICK) is a protein structural motif containing three disulfide bridges. Along with the sections of polypeptide between them, two disulfides form a loop through which the third disulfide bond (linking the 3rd and 6th cysteine in the sequence) passes, forming a knot (thus the alternate name knottin). The motif is common in invertebrate toxins such as those from arachnids and molluscs. The motif is also found in some inhibitor proteins found in plants, but the plant and animal motifs are thought to be a product of convergent evolution. The ICK motif is a very stable protein structure which is resistant to heat denaturation and proteolysis. ICK peptide components of venoms target voltage-gated ion channels but members of the family also act as antibacterial and haemolytic agents. Plant ICK proteins are often protease inhibitors. Because of their stability, ICK motifs are being developed as possible therapeutics. 
The mammalian proteins Agouti signalling peptide and Agouti related peptide are the only know mammalian examples of this motif. Both are neuropeptides involved in cell signalling. The former is responsible for hair (fur) colouration.
The motif is similar to the cyclic cystine knot or cyclotide, but lacks the cyclisation of the polypeptide backbone which is present in the latter family. The growth factor cystine knot (GFCK) shares the motif but its topology is such that it is the bond between the first and fourth disulphide which threads through the loop.
Proteins which contain the ICK motif
- Agouti related peptide
- Agouti signalling peptide
- Albumin I
- Theraphosa leblondi toxin
- He, W. J.; Chan, L. Y.; Clark, R. J.; Tang, J.; Zeng, G. Z.; Franco, O. L.; Cantacessi, C.; Craik, D. J.; Daly, N. L.; Tan, N. H. (2013). "Novel Inhibitor Cystine Knot Peptides from Momordica charantia". In Driscoll, Paul C. PLoS ONE 8 (10): e75334. doi:10.1371/journal.pone.0075334. PMC 3792974. PMID 24116036.
- Zhu, S.; Darbon, H.; Dyason, K.; Verdonck, F.; Tytgat, J. (2003). "Evolutionary origin of inhibitor cystine knot peptides". The FASEB Journal 17 (12): 1765–1767. doi:10.1096/fj.02-1044fje. PMID 12958203.
- Daly, N. L.; Craik, D. J. (2011). "Bioactive cystine knot proteins". Current Opinion in Chemical Biology 15 (3): 362–368. doi:10.1016/j.cbpa.2011.02.008. PMID 21362584.
- Craik, D. J.; Daly, N. L.; Waine, C. (2001). "The cystine knot motif in toxins and implications for drug design". Toxicon : official journal of the International Society on Toxinology 39 (1): 43–60. doi:10.1016/S0041-0101(00)00160-4. PMID 10936622.
- Baeriswyl, V.; Heinis, C. (2013). "Polycyclic Peptide Therapeutics". ChemMedChem 8 (3): 377–384. doi:10.1002/cmdc.201200513. PMID 23355488.
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