The KNOTTIN database

Knottins are intriguing miniproteins with strong potential in drug design

Welcome to the KNOTTIN database
Database 2009 built from UniProt Knowledgebase Release 15.0

News

  • September 2009 :
    Database update:
     - 30 families, 155 structures, 1621 sequences.
    Knottin classification:
     - Sequences are classified into families according to Cysteine IV position, origin and/or function.
    • - 3 new potential families have been added (Algae, Bacteria, Trichoplax)
    • - 2 previous families, Scorpion3 and Terebra, were merged with Scorpion2 and Conotoxin1, respectively.
    • - 2 previous families, Insect antimicrobial and Phenoloxidase inhibitor, were renamed as Insect1 and Insect2 respectively.

  • June 2008 :
    Database update:
     - 28 families, 148 structures, 1246 sequences.
     - Since they are no more supported by the PDB, theoretical models have been removed.
    Cyclic knottins:
     - In the standardized alignments, cyclic knottins are now truncated to the postulated mature peptides.
    • This modification is not applied to fragments or linear analogs.
    • NB1 Standardized alignments are accessible via: 'Search Database > Selection > Get standardized alignments'.
    • NB2 Both the full sequence and the 2D representation (Collier de Perles) of the putative cyclic mature sequence are available on the individual knottin cards via: 'Search Database (Sequence database) > Green buttons '.

  • October 2007 :
    Structures can be viewed with the Jmol applet:
     - Each structure can be displayed using the Jmol link in the 'Structure' tabular outputs.
     - Structural superimpositions are available:
       1 - Select structures from tabular outputs using checkboxes or the 'Select All' button
       2 - choose the "Structural superimposition" radio button
       3 - click on the "GET" button
     - Knotted cysteines are labeled, and loops are colored as follows:
       (a)=green; b=coral; c=aquamarine; (d)=lightblue; e=hotpink

  • September 2007 :
    The Tool menu has been updated:
     - Knoter3d determines if a 3D structure is a knottin.
     - Knoter1d predicts if a protein sequence is a knottin.
     - Standardized alignments and "Colliers de Perles" are available.
    Alignments can now be downloaded as:
     - msf, selex, pir or fasta formatted text.
     - sequence logo (weblogo).
    All knottins in the database (sequences and 3D structures) are renumbered according to the standard knottin numbering.
     - To get standardized alignments use the 'Search Database' menu, then the 'Get alignment' button.
     - To get classical pre-compiled alignments use the 'Sequences' menu.
     - Sequences or structures can be searched or sorted based on nomenclature (loop lengthes).

Current Statistics


FamilyCys IVSequences3D Structures
#OrganismsNMRX-RayOrganisms
All families16213621401561
Agouti-related 61 118 90 4 0 1
Alpha-amylase inhibitor 61 1 1 2 1 2
Algae 61 1 1 0 0 0
Bacteria 61 3 3 0 0 0
Bug 61 3 3 2 0 2
Carboxypeptidase inhibitor 77 13 4 2 1 2
Conotoxin1 61 440 52 29 0 8
Conotoxin2 78 5 5 1 0 1
Conotoxin3 77 1 1 0 0 0
Horseshoe crab 61 5 1 3 0 1
Cyclotide 78 165 22 24 1 8
Fungi1 77 12 6 0 0 0
Fungi2 61 20 11 0 0 0
Gurmarin-like 61 1 1 2 0 1
Insect1 61 11 4 1 0 1
Insect2 61 22 15 0 0 0
Maize 78 8 1 0 0 0
Plant antimicrobial 61 13 6 1 0 1
Plant defensin 63 2 1 1 0 1
Plant toxin 78 28 17 2 0 2
Scorpion1 61 7 6 2 0 1
Scorpion2 63 47 14 4 0 4
Spider 61 593 49 48 0 14
Sponge 61 1 1 0 0 0
Serine protease inhibitor1 78 36 16 10 12 10
Serine protease inhibitor2 61 4 2 0 0 0
Trematoda 61 12 1 0 0 0
Trichoplax 61 1 1 0 0 0
Virus1 61 24 7 2 0 1
Virus2 61 24 20 0 0 0

Loop Statistics






What are knottins

Knottins are small disulfide-rich proteins characterized by a very special "disulfide through disulfide knot"

  • This knot is achieved when one disulfide bridge crosses the macrocycle formed by the two other disulfides and the interconnecting backbone.
  • The knot implies that knottins contain at least 3 disulfide bridges
  • The structural family of knottins have the disulfide between cysteines III and VI (orange) going through disulfides I-IV and II-V (yellow).
  • The growth factor cystine knots also contain a knot but the connectivity is different and they cannot be superimposed onto knottins. These proteins belong to a distinct structural family not described in this site.
  • Knottins are sometime refered to as "Inhibitor Cystine Knots"


Disulfide connectivity in
Knottins


Disulfide connectivity in
Growth Factor cystine knots


Schematic representation of
Knottins


Schematic representation of
Growth Factor cystine knots


The knottin structural family includes several unrelated families

  • Protease inhibitors from plants
  • Peptides from the Rubiaceae and the Violaceae plant families
  • Toxins from cone snail, spider, bug, horseshoe crab, scorpion
  • Gurmarin-like peptides, human Agouti-related protein ...
  • Antimicrobial peptides

A number of small disulfide-rich proteins may look like Knottins, but are not Knottins simply because there is no knot in there (see a list here).


The knottin fold is an attractive scaffold for drug design

  • it is small and easily accessible to chemical synthesis
  • it is very stable, thanks to the high disulfide content and the knotted topology
  • it is strongly sequence tolerent