Indeed, the knottins very low sequence identity between families and high sequence plasticity (except for the cysteines) require specific procedures to correctly identify and classify these proteins. Our knottin-dedicated database is valuable given the specific properties of these miniproteins in terms of sequence, structure and function. Data about cyclotides can also be found in the more specialized database CyBase ( 5, 6). Since its launch in 2004, our KNOTTIN database ( 4) concentrates sequences, structures and bibliographical data about ICKs, except the few proteins belonging to the growth factor cystine-knots group. The ICK family is made of three groups: (i) knottins, which represents the majority of ICKs-so that the two names are often used interchangeably-and are characterized by having disulfide bonds between the knot-forming cysteines III and VI going through cystines I-IV and II-V (ii) cyclotides, which have the same disulfide connectivity as knottins, but have their backbone cyclized via an N-terminal to C-terminal peptide bond and (iii) growth factor cystine-knots, which is the smallest group of the ICK family and includes proteins with a different connectivity than knottins and cyclotides. Examples are the US FDA-approved Linzess ® (linaclotide, Allergan/Ironwood Pharmaceuticals ( 3), which is used to treat irritable bowel disease with constipation, and Prialt ® (ziconotide, Azur Pharma which is used to treat chronic pain. All these properties have lead to use ICKs as scaffolds for the engineering of various pharmaceutical and imaging agents ( 1, 2).
The loops connecting the disulfide bridges show a high variability of sequence, which results in a broad range of functions covered by ICKs, from channel blockage to inhibition of enzymes. ICKs are ∼30–50 residue long, which make them easily accessible to chemical synthesis. They are characterized by the presence of at least three interwoven disulfide bridges, which form an intramolecular knot and confer them structural and functional resistance to high temperature, enzymatic degradation, extreme pH and mechanical stress. Inhibitor cystine-knots (ICKs) form a family of ultra-stable miniproteins, found in a wide variety of organisms, with confirmed and potential medical applications. Finally, we report how our web resource has proved usefulness for the researchers working on ICKs, and how the new version of the KNOTTIN website will continue to serve this active community. In addition to the new features, this article describes how KNOTTIN has seen its size multiplied over the past ten years (since its last publication), notably with the recent inclusion of predicted ICKs structures.
#Scaffold knot upgrade#
Here, we present a major upgrade of our database, both in terms of data content and user interface. The website also provides access to bibliographic data and to computational tools that have been specifically developed for ICKs. Since 2004, the KNOTTIN database ( has been gathering standardized information about knottin sequences, structures, functions and evolution. These widespread and functionally diverse proteins are characterized by the presence of three interwoven disulfide bridges in their structure, which form a unique pseudoknot. Knottins, or inhibitor cystine knots (ICKs), are ultra-stable miniproteins with multiple applications in drug design and medical imaging.
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