Summary: Cyclotide family

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Cyclotides Edit Wikipedia article

Cyclotide family

Figure 1. Structure and sequence of the prototypic cyclotide kalata B1

Identifiers

Symbol

Cyclotide

Available protein structures:
Pfam	structures
PDB	RCSB PDB; PDBe
PDBsum	structure summary

Cyclotides are small disulfide rich peptides isolated from plants.^[1] Typically containing 28-37 amino acids, they are characterized by their head-to-tail cyclised peptide backbone and the interlocking arrangement of their three disulfide bonds. These combined features have been termed the cyclic cystine knot (CCK) motif (Figure 1). To date, over 100 cyclotides have been isolated and characterized from species of the Rubiaceae, Violaceae, and Cucurbitaceae families. Cyclotides have also been identified in agriculturally important families such as the Fabaceae and Poaceae.,^[2]

[edit] Cyclotide structure

Cyclotides have a well-defined three-dimensional structure as a result of their interlocking disulfide bonds and cyclic peptide backbone. Backbone loops and selected residues are labeled on the structure to help orientation. The amino acid sequence (single letter amino acid representation) for this peptide is indicated on the sequence diagram to the right. One of the interesting features of cyclic peptides is that knowledge of the peptide sequence does not reveal the ancestral head and tail; knowledge of the gene sequence is required for this.^[3] In the case of kalata B1 the indicated glycine (G) and asparagine (N) amino acids are the terminal residues that are linked in a peptide bond to cyclise the peptide.

[edit] Biological significance

Figure 2. The stunting effect of kalata B1 on growth and development of Helicoverpa punctigera, a caterpillar from the Lepidopteran order.^a

Cyclotides have been reported to have a wide range of biological activities, including anti-HIV, insecticidal, anti-tumour, antifouling, anti-microbial, hemolytic, neurotensin antagonism, trypsin inhibition, and uterotonic activities.^[4]^[5]^[6] An ability to induce uterine contractions was what prompted the initial discovery of kalata B1.^[7]

The potent insecticidal activity of cyclotides kalata B1 and kalata B2 has prompted the belief that cyclotides act as plant host-defence agents (Figure 2). The observations that dozens or more cyclotides may be present in a single plant and the cyclotide architecture comprises a conserved core onto which a series of hypervariable loops is displayed suggest that, cyclotides may be able to target many pests/pathogens simultaneously.

[edit] A Serendipitous Discovery

Kalata (2002) by Julian Voss-Andreae. The pictured sculpture is based on the atomic coordinates of kalata B1.^[8]

Figure 3. A tea made from the plant Oldenlandia affinis was used by an African tribe to induce labor and facilitate childbirth

During a Red Cross relief mission in the Democratic Republic of Congo during the 1960s, a Norwegian doctor, Lorents Gran, noted that during labor African women used a medicinal tea made from the leaves of the plant Oldenlandia affinis (Figure 3) to induce labor and facilitate childbirth.^[9] The active ingredient was later determined to be a peptide, named kalata B1, after the traditional name for the native medicine, kalata-kalata. Although in vivo studies in rats confirmed the uterotonic activity of the purified peptide, it was another 20 years before the cyclic cystine knot motif and structure of the purified peptide were elucidated.^[10]

[edit] Cyclotide amino-acid sequences

Analysis of the suite of known cyclotides reveals many sequence homologies that are important for understanding their unique physico-chemical properties and bioactivities. Table 1 presents a selection of cyclotides.

The cyclotides fall into two main structural subfamilies. Moebius cyclotides, the less common of the two, contain a cis-proline in loop 5 that induces a local 180° backbone twist (hence likening it to a Möbius strip), whereas bracelet cyclotides do not. There is smaller variation in sequences within these subfamilies than between them. A third subfamily of cyclotides are trypsin inhibitors and are more homologous to a family of non-cyclic trypsin inhibitors from squash plants known as knottins^[11] than they are to the other cyclotides.

It is convenient to discuss sequences in terms of the backbone segments, or loops, between successive cysteine residues. The six cysteine residues are absolutely conserved throughout the cyclotide suite and presumably contribute to the preservation of the CCK motif. Although the cysteines appear essential to maintaining the overall fold, several other residues that are highly conserved in cyclotides are thought to provide additional stability.^[12]

Throughout the known cyclotides loop 1 is the most conserved. Apart from the six cysteine residues, the glutamic acid and serine/threonine residues of loop 1 are the only residues to have 100% identity across the bracelet and Möbius subfamilies. Furthermore the remaining residue of this loop exhibits only a conservative change i.e. glycine/alanine. This loop is believed to play an important role in stabilizing the cyclotide structure through hydrogen bonding with residues from loops 3 and 5.

Loops 2-6 also have highly conserved features, including the ubiquitous presence of just a single amino acid in loop 4 that is likely involved in sidechain-sidechain hydrogen bonding. Other conserved residues include a hydroxyl-containing residue in loop 3, a glycine residue in the final position of loop 3, a basic and a proline residue in the penultimate position in loop 5 of bracelet and Möbius cyclotides respectively, and an asparagine (or occasionally aspartic acid) residue at the putative cyclisation^[3]^[13]^[14] point in loop 6. It is of interest to note that not only are certain residues highly conserved, but the backbone and side chain angles are as well.

With recent screening programs suggesting that the number of cyclotide sequences may soon reach the thousands,^[15] a database, CyBase, has been developed that offers the opportunity for comparisons of sequences and activity data for cyclotides. Several other families of circular proteins are known in bacteria, plants and animals and are also included in CyBase.^[16]

Table 1. A selection of cyclotide sequences and sources

[edit] Biosynthesis of cyclotides

Figure 4. Schematic representation of the cyclotide precursors Oak1 and Oak4 and proposed mechanism of biosynthesis.^[17]

Plants are a rich source of cyclic peptides, with the vast majority of these molecules being produced via non-ribosomal biosynthetic pathways. In contrast, the cyclotides are gene-coded products generated via processing of a larger precursor protein.^[3] The gene for the first such precursor is Oak1 (Oldenlandia affinis kalata clone number 1), which was shown to be responsible for the synthesis of kalata B1.^[13] Figure 4 illustrates the generic configuration of the precursor protein, which consist of an endoplasmic reticulum signal sequence, a non-conserved pro-region, a highly conserved region known as the N-terminal repeat (NTR), the mature cyclotide domain and finally a short hydrophobic C-terminal tail. The cyclotide domain may contain either one cyclotide sequence, as in the case of Oak1, or multiple copies separated by additional NTR sequences as seen for Oak2 and Oak4. In precursor proteins containing multiple cyclotide domains these can either be all identical sequences, as is the case for Oak4, or they can be different cyclotides as in Oak2 which contains sequences corresponding to kalata B3 and B6.

[edit] Applications

The remarkable stability of cyclotides means that they have an exciting range of potential applications centred on either their intrinsic biological activities or the possibility of using the CCK motif as a scaffold for stabilizing biologically active epitopes.^[18] Interest in these has recently intensified with the publications of a chemical methodology capable of synthetically producing cyclotides with high yields,^[19] and the amenability of the CCK framework to amino-acid substitutions.^[20] But for molecules to be useful in a therapeutic setting they require useful biopharmaceutical characteristics such as resistance to proteolysis and membrane permeability. A recent study on related cystine knot proteins as drug candidates showed that cystine knots do permeate well through rat small intestinal mucosa relative to non-cystine knot peptide drugs such as insulin and bacitracin.^[21] Furthermore, enzymatic digestion of cystine knot peptide drugs was associated with only a few proteases and it was suggested that this limitation may be overcome by mutating out particular cleavage sites. Thus, certain cystine knot proteins satisfy the basic criteria for drug delivery and represent exciting novel candidates as scaffolds for peptide drug delivery.^[21] The diverse range of intrinsic activities of cyclotides also continues to hold promise for a wide range of applications in the agricultural fields.

[edit] Notes

a.^ A diet containing 0.8 μmol/g kalata B1 for 16 days significantly hindered development of caterpillar larvae compared with larvae on a diet free of kalata B1. Although no mortality was observed in the first six days for larvae fed the kalata B1 diet, 50% failed to survive past day sixteen. Those that did survive failed to progress pass the first instar stage of development and on average weighed 3.3 mg compared with larvae on the kalata B1 free diet that achieved fifth instar and weighed on average 284 mg ^[13]

[edit] See also

[edit] References

^ Craik DJ, Daly NL, Bond T, Waine C (1999). "Plant cyclotides: A unique family of cyclic and knotted proteins that defines the cyclic cystine knot structural motif". J. Mol. Biol. 294 (5): 1327–36. doi:10.1006/jmbi.1999.3383. PMID 10600388.
^ Poth AG, Colgrave ML, Lyons RE, Daly NL, Craik DJ (2011). "Discovery of an unusual biosynthetic origin for circular proteins in legumes". Proceedings of the National Academy of Sciences 108 (25): 10127–10132. doi:10.1073/pnas.1103660108. PMC 3121837. PMID 21593408. //www.ncbi.nlm.nih.gov/pmc/articles/PMC3121837/.
^ ^a ^b ^c Dutton JL, Renda RF, Waine C, et al. (2004). "Conserved structural and sequence elements implicated in the processing of gene-encoded circular proteins". J. Biol. Chem. 279 (45): 46858–67. doi:10.1074/jbc.M407421200. PMID 15328347.
^ Craik DJ, Daly NL, Mulvenna J, Plan MR, Trabi M (2004). "Discovery, structure and biological activities of the cyclotides". Curr. Protein Pept. Sci. 5 (5): 297–315. doi:10.2174/1389203043379512. PMID 15544527.
^ Göransson U, Sjögren M, Svangård E, Claeson P, Bohlin L (2004). "Reversible antifouling effect of the cyclotide cycloviolacin O2 against barnacles". J. Nat. Prod. 67 (8): 1287–90. doi:10.1021/np0499719. PMID 15332843.
^ Gustafson KR, McKee TC, Bokesch HR (2004). "Anti-HIV cyclotides". Curr. Protein Pept. Sci. 5 (5): 331–40. doi:10.2174/1389203043379468. PMID 15544529.
^ Gran L (1970). "An oxytocic principle found in Oldenlandia affinis DC An indigenous, Congolese drug kalata-kalataused to accelerate delivery". Medd. Nor. Farm. Selsk 32 (12): 173–80. http://www.popline.org/docs/0103/702847.html.^{[dead link]}
^ Voss-Andreae, J (2005). "Protein Sculptures: Life's Building Blocks Inspire Art". Leonardo 38: 41–45. doi:10.1162/leon.2005.38.1.41.
^ Gran L, Sandberg F, Sletten K (2000). "Oldenlandia affinis (R&S) DC. A plant containing uteroactive peptides used in African traditional medicine". J Ethnopharmacol 70 (3): 197–203. doi:10.1016/S0378-8741(99)00175-0. PMID 10837983.
^ Saether O, Craik DJ, Campbell ID, Sletten K, Juul J, Norman DG (1995). "Elucidation of the primary and three-dimensional structure of the uterotonic polypeptide kalata B1". Biochemistry 34 (13): 4147–58. doi:10.1021/bi00013a002. PMID 7703226.
^ Chiche L, Heitz A, Gelly JC, et al. (2004). "Squash inhibitors: from structural motifs to macrocyclic knottins". Curr. Protein Pept. Sci. 5 (5): 341–349. doi:10.2174/1389203043379477. PMID 15551519.
^ Rosengren KJ, Daly NL, Plan MR, Waine C, Craik DJ (2003). "Twists, knots, and rings in proteins. Structural definition of the cyclotide framework". J. Biol. Chem. 278 (10): 8606–16. doi:10.1074/jbc.M211147200. PMID 12482868.
^ ^a ^b ^c Jennings C, West J, Waine C, Craik D, Anderson M (2001). "Biosynthesis and insecticidal properties of plant cyclotides: The cyclic knotted proteins from Oldenlandia affinis". Proc. Natl. Acad. Sci. U.S.A. 98 (19): 10614–9. doi:10.1073/pnas.191366898. PMC 58514. PMID 11535828. //www.ncbi.nlm.nih.gov/pmc/articles/PMC58514/.
^ Ireland DC, Colgrave ML, Nguyencong P, Daly NL, Craik DJ (2006). "Discovery and characterization of a linear cyclotide from Viola odorata: implications for the processing of circular proteins". J. Mol. Biol. 357 (5): 1522–35. doi:10.1016/j.jmb.2006.01.051. PMID 16488428.
^ Simonsen SM, Sando L, Ireland DC, et al. (2005). "A Continent of Plant Defense Peptide Diversity: Cyclotides in Australian Hybanthus (Violaceae)". Plant Cell 17 (11): 3176–89. doi:10.1105/tpc.105.034678. PMC 1276036. PMID 16199617. //www.ncbi.nlm.nih.gov/pmc/articles/PMC1276036/.
^ Craik DJ (2006). "Chemistry. Seamless proteins tie up their loose ends". Science 311 (5767): 1563–4. doi:10.1126/science.1125248. PMID 16543448.
^ Gruber CW, Cemazar M, Anderson MA, Craik DJ (2007). "Insecticidal plant cyclotides and related cystine knot toxins". Toxicon 49 (4): 561–75. doi:10.1016/j.toxicon.2006.11.018. PMID 17224167.
^ Craik DJ, Simonsen S, Daly NL (2002). "The cyclotides: novel macrocyclic peptides as scaffolds in drug design". Curr Opin Drug Discov Devel 5 (2): 251–60. PMID 11926131.
^ Gunasekera S, Daly NL, Anderson MA, Craik DJ (2006). "Chemical synthesis and biosynthesis of the cyclotide family of circular proteins". IUBMB Life 58 (9): 515–24. doi:10.1080/15216540600889532. PMID 17002979.
^ Craik DJ, Cemazar M, Daly NL (2006). "The cyclotides and related macrocyclic peptides as scaffolds in drug design". Curr Opin Drug Discov Devel 9 (2): 251–60. PMID 16566295.
^ ^a ^b Werle M, Schmitz T, Huang HL, Wentzel A, Kolmar H, Bernkop-Schnürch A (2006). "The potential of cystine-knot microproteins as novel pharmacophoric scaffolds in oral peptide drug delivery". J Drug Target 14 (3): 137–46. doi:10.1080/10611860600648254. PMID 16753827.

[edit] Further reading

Shenkarev ZO, Nadezhdin KD, Sobol VA, Sobol AG, Skjeldal L, Arseniev AS (2006). "Conformation and mode of membrane interaction in cyclotides. Spatial structure of kalata B1 bound to a dodecylphosphocholine micelle". FEBS J. 273 (12): 2658–72. doi:10.1111/j.1742-4658.2006.05282.x. PMID 16817894.
Sancheti H, Camarero JA (September 2009). ""Splicing up" drug discovery. Cell-based expression and screening of genetically-encoded libraries of backbone-cyclized polypeptides". Adv. Drug Deliv. Rev. 61 (11): 908–17. doi:10.1016/j.addr.2009.07.003. PMID 19628015.
Gerlach SL, Mondal D (2012). "The bountiful biological activities of cyclotides". Chron Young Sci 3: 169–177. http://www.cysonline.org/article.asp?issn=2229-5186;year=2012;volume=3;issue=3;spage=169;epage=177;aulast=Gerlach.

[edit] External links

Cybase

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.

Cyclotide family Provide feedback

This family contains a set of cyclic peptides with a variety of activities. The structure consists of a distorted triple-stranded beta-sheet and a cysteine-knot arrangement of the disulfide bonds [2]. Cyclotides can be separated into two subfamilies, namely bracelet and moebius. The bracelet cyclotide subfamily tends to contain a larger number of positively charged residues and has a bracelet-like circularisation of the backbone [2]. The moebius cyclotide subfamily contains a backbone twist due to a cis-Pro peptide bond and may conceptually be regarded as a molecular Moebius strip [2].

Literature references

Daly NL, Koltay A, Gustafson KR, Boyd MR, Casas-Finet JR, Craik DJ; , J Mol Biol 1999;285:333-345.: Solution structure by NMR of circulin A: a macrocyclic knotted peptide having anti-HIV activity. PUBMED:9878410 EPMC:9878410
Craik DJ, Daly NL, Bond T, Waine C; , J Mol Biol 1999;294:1327-1336.: Plant cyclotides: A unique family of cyclic and knotted proteins that defines the cyclic cystine knot structural motif. PUBMED:10600388 EPMC:10600388

External database links

PANDIT:	PF03784
Pseudofam:	PF03784
SCOP:	1kal
SYSTERS:	Cyclotide

This tab holds annotation information from the InterPro database.

InterPro entry IPR005535

Cyclotides (cyclo peptides) are plant peptides of ~30 amino acids with a head to-tail cyclic backbone and six cysteine residues involved in three disulphide bonds. The cyclotides are extremely resistant to proteolysis and are remarkably stable. Cyclotides display a diverse range of biological activities, including uterotonic activity, inhibition of neurotensin binding, hemolytic, anti-HIV and anti-microbial activity. This range of biological activities makes cyclotides amenable to potential pharmaceutical and agricultural applications. Although their precise role in plants has not yet been reported, it appears that they are most likely present as defence molecules [PUBMED:10600388, PUBMED:12482862, PUBMED:12482868, PUBMED:12946412].

The three-dimensional structure of cyclotides is compact and contains a number of beta-turns, three beta strands arranged in a distorted triple-stranded beta-sheet, a short helical segment, and a network of disulphide bonds which form a cystine knot. The cystine knot consists of an embedded ring in the structure, formed by two disulphide bonds and their connecting backbone segments is threaded by a third disulphide bond. Although the cystine knot motif is now well known in a wide variety of proteins, the cyclotides remain as the only example in which a cystine knot is embedded within a circular protein backbone, a motif that is referred to as the cyclic cystine knot (CCK) [PUBMED:10600388, PUBMED:12482862, PUBMED:12482868, PUBMED:12946412].

Cyclotides can be separated into two sub-families, one of which tends to contain a larger number of positively charged residues and has a bracelet-like circularisation of the backbone. The second subfamily contains a backbone twist due to a cis-Pro peptide bond and may conceptually be regarded as a molecular Moebius strip [PUBMED:10600388, PUBMED:12482868]. Bracelet and Moebius families of cyclotides possess a Knottin scaffold. The cyclotide family of proteins is abundant in plants from the Rubiaceae and Violaceae families and includes:

Kalata B1.
Circulins.
Cyclopsychotride A.
Cycloviolacin O1.

Gene Ontology

The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.

Biological process

defense response (GO:0006952)

Domain organisation

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Alignments

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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RP15/RP35/RP55/RP75: Representative Proteomes (RPs) at 15%, 35%, 55% and 75% co-membership thresholds
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meta: alignment generated by searching the metagenomics sequence database using the family HMM

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	Seed (30)	Full (259)	Representative proteomes				NCBI (274)	Meta (0)
	Seed (30)	Full (259)	RP15 (0)	RP35 (0)	RP55 (0)	RP75 (0)	NCBI (274)	Meta (0)
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HTML	View	View
PP/heatmap	₁	View
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¹Cannot generate PP/Heatmap alignments for seeds; no PP data available

Key: available, not generated, — not available.

Format an alignment

	Seed (30)	Full (259)	Representative proteomes				NCBI (274)	Meta (0)
	Seed (30)	Full (259)	RP15 (0)	RP35 (0)	RP55 (0)	RP75 (0)	NCBI (274)	Meta (0)
Alignment:
Format:
Order:	Tree Alphabetical
Sequence:	Inserts lower case All upper case
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Download/view:	Download View

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We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.

	Seed (30)	Full (259)	Representative proteomes				NCBI (274)	Meta (0)
	Seed (30)	Full (259)	RP15 (0)	RP35 (0)	RP55 (0)	RP75 (0)	NCBI (274)	Meta (0)
Raw Stockholm	Download	Download					Download
Gzipped	Download	Download					Download

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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Trees

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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

Seed source:

[1]

Previous IDs:

none

Type:

Domain

Author:

Bateman A

Number in seed:

30

Number in full:

259

Average length of the domain:

29.80 aa

Average identity of full alignment:

57 %

Average coverage of the sequence by the domain:

44.52 %

HMM information

HMM build commands:

build method: hmmbuild -o /dev/null HMM SEED

search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq

Model details:

Parameter	Sequence	Domain
Gathering cut-off	20.3	20.3
Trusted cut-off	20.5	20.5
Noise cut-off	17.2	19.8

Model length:

30

Family (HMM) version:

8

Download:

download the raw HMM for this family

Species distribution

Sunburst
Tree

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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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Unmapped species names

The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.

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Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.

Too many species/sequences

For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.

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Tree controls

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The tree shows the occurrence of this domain across different species. More...

Species trees

We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.

Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.

If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.

Interactive tree

For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.

We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.

Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.

We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.

You can use the tree controls to manipulate how the interactive tree is displayed:

show/hide the summary boxes
highlight species that are represented in the seed alignment
expand/collapse the tree or expand it to a given depth
select a sub-tree or a set of species within the tree and view them graphically or as an alignment
save a plain text representation of the tree

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Please note: for large trees this can take some time. While the tree is loading, you can safely switch away from this tab but if you browse away from the family page entirely, the tree will not be loaded.

Structures

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 Cyclotide domain has been found. There are 33 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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Archea	Eukaryota
Bacteria	Other sequences
Viruses	Unclassified
Viroids	Unclassified sequence

Family: Cyclotide (PF03784)

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