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14  structures 506  species 6  interactions 1788  sequences 23  architectures

Family: Cys_knot (PF00007)

Summary: Cystine-knot domain

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This is the Wikipedia entry entitled "Cystine knot". More...

Cystine knot Edit Wikipedia article

Cystine-knot domain
PDB 1hcn EBI.jpg
Structure of human chorionic gonadotropin.[1]
Symbol Cys_knot
Pfam PF00007
Pfam clan CL0079
InterPro IPR006208
SCOP 1hcn

A cystine knot is a protein structural motif containing three disulfide bridges (formed from pairs of cysteine molecules). The sections of polypeptide that occur between two of them form a loop through which a third disulfide bond passes, forming a rotaxane substructure. It occurs in many proteins across many species and provides considerable structural stability.[2] There are three types of cystine knot, which differ in the topology of the disulfide bonds:[3]

The growth factor cystine knot (GFCK) was first observed in the structure of Nerve Growth Factor, solved by X-ray crystallography and published in 1991 by Tom Blundell in Nature.[4] All GFCK structures that have been determined are dimeric, but their dimerization modes in different classes are different.[5]


  1. ^ Wu H, Lustbader JW, Liu Y, Canfield RE, Hendrickson WA (June 1994). "Structure of human chorionic gonadotropin at 2.6 A resolution from MAD analysis of the selenomethionyl protein". Structure 2 (6): 545–58. doi:10.1016/s0969-2126(00)00054-x. PMID 7922031. 
  2. ^
  3. ^ 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.  edit
  4. ^ PDB: 1bet​; McDonald NQ, Lapatto R, Murray-Rust J, Gunning J, Wlodawer A, Blundell TL (December 1991). "New protein fold revealed by a 2.3-A resolution crystal structure of nerve growth factor". Nature 354 (6352): 411–4. doi:10.1038/354411a0. PMID 1956407. 
  5. ^ Jiang X, Dias JA, He X (Aug 2013). "Structural biology of glycoprotein hormones and their receptors: Insights to signaling". Mol Cell Endocrinol 382 (1): 424–51. doi:10.1016/j.mce.2013.08.021. PMID 24001578. 

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

Cystine-knot domain Provide feedback

The family comprises glycoprotein hormones and the C-terminal domain of various extracellular proteins. It is believed to be involved in disulfide-linked dimerisation.

Literature references

  1. Bork P; , FEBS Lett 1993;327:125-130.: The modular architecture of a new family of growth regulators related to connective tissue growth factor. PUBMED:7687569 EPMC:7687569

Internal database links

External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR006208

This domain is found at the C-terminal of glycoprotein hormones and various extracellular proteins. It is believed to be involved in disulphide-linked dimerisation [PUBMED:7687569].

Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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Pfam Clan

This family is a member of clan Cystine-knot (CL0079), which has the following description:

The cytokine families in this clan have the cystine-knot fold. In this 6 cysteines form three disulphide bridges that are interlinked.

The clan contains the following 10 members:

Coagulin Cys_knot DAN Hormone_6 NGF Noggin PDGF Sclerostin Spaetzle TGF_beta


We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the NCBI sequence database, and our metagenomics sequence database. More...

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We make a range of alignments for each Pfam-A family. You can see a description of each above. You can view these alignments in various ways but please note that some types of alignment are never generated while others may not be available for all families, most commonly because the alignments are too large to handle.

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You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

External links

MyHits provides a collection of tools to handle multiple sequence alignments. For example, one can refine a seed alignment (sequence addition or removal, re-alignment or manual edition) and then search databases for remote homologs using HMMER3.

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HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...


This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.

Note: You can also download the data file for the tree.

Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation View help on the curation process

Seed source: Published_alignment enriched with PDOC00234 members.
Previous IDs: none
Type: Domain
Author: Sonnhammer ELL
Number in seed: 24
Number in full: 1788
Average length of the domain: 91.20 aa
Average identity of full alignment: 27 %
Average coverage of the sequence by the domain: 42.88 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 80369284 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 21.3 21.3
Trusted cut-off 21.3 21.3
Noise cut-off 21.2 21.2
Model length: 105
Family (HMM) version: 18
Download: download the raw HMM for this family

Species distribution

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Colour assignments

Archea Archea Eukaryota Eukaryota
Bacteria Bacteria Other sequences Other sequences
Viruses Viruses Unclassified Unclassified
Viroids Viroids Unclassified sequence Unclassified sequence


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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the adjacent tab. More...

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There are 6 interactions for this family. More...

Hormone_6 Cys_knot GnHR_trans Hormone_6 LRR_8 LRRNT


For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Cys_knot domain has been found. There are 14 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.

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