Cyclotide

Last updated
Cyclotide family
Cyclotide structure.jpg
Structure and sequence of the prototypic cyclotide kalata B1
Identifiers
SymbolCyclotide
Pfam PF03784
InterPro IPR005535
PROSITE PDOC51052
SCOP2 1kal / SCOPe / SUPFAM
OPM superfamily 112
OPM protein 1nb1
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

In biochemistry, 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. To date, over 100 cyclotides have been isolated and characterized from species of the families Rubiaceae, Violaceae, and Cucurbitaceae. Cyclotides have also been identified in agriculturally important families such as the Fabaceae and Poaceae. [2] [3] [4]

Contents

Structure

Cyclotides have a well-defined three-dimensional structure due to 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. [5] 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 cyclize the peptide.

Biological function

The stunting effect of kalata B1 cyclic peptide on growth and development of Helicoverpa punctigera, a caterpillar from the Lepidopteran order. Helicoverpa size.jpg
The stunting effect of kalata B1 cyclic peptide on growth and development of Helicoverpa punctigera, a caterpillar from the Lepidopteran order.

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. [7] [8] [9] An ability to induce uterine contractions was what prompted the initial discovery of kalata B1. [10]

The potent insecticidal activity of cyclotides kalata B1 and kalata B2 has prompted the belief that cyclotides act as plant host-defence agents. 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. [11]

Amino-acid sequences

Analysis of the suite of known cyclotides reveals many sequence similarities that are important for understanding their unique physico-chemical properties, bioactivities and homology.

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 or inhibitor cystine knots [12] 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 preserving the CCK motif. Although the cysteines appear essential to maintaining the overall fold, several other residues highly conserved in cyclotides are thought to provide additional stability. [13]

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 [5] [6] [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]

A selection of cyclotide sequences and sources Cyclotides sequence table.jpg
A selection of cyclotide sequences and sources

Biosynthesis

The cyclotide precursor is comprised a hydrophobic Signal peptide that targets the precursor to the Endoplasmic Reticulum (ER), an N-terminal propeptide that then targets it to the vacuole, a cyclotide domain and a final C-terminal propeptide necessary for cyclisation.The cyclotide domain folds in the ER, after which it is trafficked to the vacuole and the cyclotide domain is cyclised by an asperginyl endopeptidase. (PDB: 1WN8, 1NB1 ) Cyclotide biosynthesis.png
The cyclotide precursor is comprised a hydrophobic Signal peptide that targets the precursor to the Endoplasmic Reticulum (ER), an N-terminal propeptide that then targets it to the vacuole, a cyclotide domain and a final C-terminal propeptide necessary for cyclisation.The cyclotide domain folds in the ER, after which it is trafficked to the vacuole and the cyclotide domain is cyclised by an asperginyl endopeptidase. ( PDB: 1WN8, 1NB1 ​)

Plants are a rich source of ribosomally-synthesised and post-translationally modified cyclic peptides. Among these, the cyclotides are gene-coded products generated via processing of a larger precursor protein. [5] 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. [6] The generic configuration of the precursor protein consists 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. [17]

Recently, the enzyme responsible for the backbone cyclization of cyclotides has been isolated from the medicinal plant Clitoria ternatea . This enzyme was named butelase 1 in accordance to the local name of the plant (Bunga Telang Ligase). Butelase 1 has been shown to cyclize the linear precursor of kalata B1 with >95% yield at a remarkable rate of 5.42×105 M−1 s−1. The ligase also cyclizes various bioactive peptides of animal origin, such as human antimicrobial peptide histatin, conotoxin from cone snail and insect antimicrobial peptide thanatin. [18]

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. [19] Interest in these has recently intensified with the publications of a chemical methodology capable of synthetically producing cyclotides with high yields, [20] [21] and the amenability of the CCK framework to amino-acid substitutions. [22] But for molecules to be useful in a therapeutic setting they require useful biopharmaceutical characteristics such as resistance to proteolysis and membrane permeability. The membrane interactive surface area and moment of the cyclotides are determinants in the prediction of their biological activities. [23] 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. [24] 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. [24] The diverse range of intrinsic activities of cyclotides also continues to hold promise for a wide range of applications in the agricultural fields against insects and nematodes, especially those from Clitoria ternatea. [25] [26]

History

Kalata (2002) by Julian Voss-Andreae. The pictured sculpture is based on the atomic coordinates of kalata B1. Kalata.jpg
Kalata (2002) by Julian Voss-Andreae. The pictured sculpture is based on the atomic coordinates of kalata B1.
A tea made from the plant Oldenlandia affinis was used by an African tribe to induce labor and facilitate childbirth Oldenlandia affinis 001.jpg
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 to induce labor and facilitate childbirth. [28] The active ingredient was later determined to be a cyclic peptide, named kalata B1, after the traditional name for the tea, 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. [29]

See also

Related Research Articles

<span class="mw-page-title-main">DD-transpeptidase</span> Bacterial enzyme

DD-transpeptidase is a bacterial enzyme that catalyzes the transfer of the R-L-αα-D-alanyl moiety of R-L-αα-D-alanyl-D-alanine carbonyl donors to the γ-OH of their active-site serine and from this to a final acceptor. It is involved in bacterial cell wall biosynthesis, namely, the transpeptidation that crosslinks the peptide side chains of peptidoglycan strands.

<span class="mw-page-title-main">Conotoxin</span> Group of neurotoxins

A conotoxin is one of a group of neurotoxic peptides isolated from the venom of the marine cone snail, genus Conus.

<span class="mw-page-title-main">Cyclic peptide</span> Peptide chains which contain a circular sequence of bonds

Cyclic peptides are polypeptide chains which contain a circular sequence of bonds. This can be through a connection between the amino and carboxyl ends of the peptide, for example in cyclosporin; a connection between the amino end and a side chain, for example in bacitracin; the carboxyl end and a side chain, for example in colistin; or two side chains or more complicated arrangements, for example in alpha-amanitin. Many cyclic peptides have been discovered in nature and many others have been synthesized in the laboratory. Their length ranges from just two amino acid residues to hundreds. In nature they are frequently antimicrobial or toxic; in medicine they have various applications, for example as antibiotics and immunosuppressive agents. Thin-Layer Chromatography (TLC) is a convenient method to detect cyclic peptides in crude extract from bio-mass.

<span class="mw-page-title-main">Beta hairpin</span>

The beta hairpin is a simple protein structural motif involving two beta strands that look like a hairpin. The motif consists of two strands that are adjacent in primary structure, oriented in an antiparallel direction, and linked by a short loop of two to five amino acids. Beta hairpins can occur in isolation or as part of a series of hydrogen bonded strands that collectively comprise a beta sheet.

<span class="mw-page-title-main">Trefoil knot fold</span>

The trefoil knot fold is a protein fold in which the protein backbone is twisted into a trefoil knot shape. "Shallow" knots in which the tail of the polypeptide chain only passes through a loop by a few residues are uncommon, but "deep" knots in which many residues are passed through the loop are extremely rare. Deep trefoil knots have been found in the SPOUT superfamily. including methyltransferase proteins involved in posttranscriptional RNA modification in all three domains of life, including bacterium Thermus thermophilus and proteins, in archaea and in eukaryota.

<span class="mw-page-title-main">Cystine knot</span> Protein structural motif

A cystine knot is a protein structural motif containing three disulfide bridges. The sections of polypeptide that occur between two of them form a loop through which a third disulfide bond passes, forming a rotaxane substructure. The cystine knot motif stabilizes protein structure and is conserved in proteins across various species. There are three types of cystine knot, which differ in the topology of the disulfide bonds:

<span class="mw-page-title-main">Alanine scanning</span> Molecular biology technique

In molecular biology, alanine scanning is a site-directed mutagenesis technique used to determine the contribution of a specific residue to the stability or function of a given protein. Alanine is used because of its non-bulky, chemically inert, methyl functional group that nevertheless mimics the secondary structure preferences that many of the other amino acids possess. Sometimes bulky amino acids such as valine or leucine are used in cases where conservation of the size of mutated residues is needed.

Theta-defensins are a family of mammalian antimicrobial peptides. They are found in non-human 'Old World' primates, but not in human, gorilla, bonobo, and chimpanzee.

Hedyotis (starviolet) is a genus of flowering plants in the family Rubiaceae. Many species of this genus such as Hedyotis biflora, H. corymbosa and H. diffusa are well known medicinal plants. Hedyotis is native to tropical and subtropical Asia and to islands of the northwest Pacific. It comprises about 115 species. The type species for the genus is Hedyotis fruticosa.

<span class="mw-page-title-main">Inhibitor cystine knot</span>

An inhibitor cystine knot is a protein structural motif containing three disulfide bridges. Knottins are one of three folds in the cystine knot motif; the other closely related knots are the growth factor cystine knot (GFCK) and the cyclic cystine knot. Types include a) cyclic mobius, b) cyclic bracelet, c) acyclic inhibitor knottins. Cystine knot motifs are found frequently in nature in a plethora of plants, animals, and fungi and serve diverse functions from appetite suppression to anti-fungal activity.

Ribosomally synthesized and post-translationally modified peptides (RiPPs), also known as ribosomal natural products, are a diverse class of natural products of ribosomal origin. Consisting of more than 20 sub-classes, RiPPs are produced by a variety of organisms, including prokaryotes, eukaryotes, and archaea, and they possess a wide range of biological functions.

Split-intein circular ligation of peptides and proteins (SICLOPPS) is a biotechnology technique that permits the creation of cyclic peptides. These peptides are produced by ribosomal protein synthesis, followed by an intein-like event that splices the protein into a loop. By contrast with the nonribosomal peptide synthetases that produces some cyclic peptides like gramicidin S, SICLOPPS offers the advantage that the peptides' structure can be encoded by DNA in a simple manner according to the genetic code, but for this reason it imposes limitations on the types of amino acids incorporated that are comparable to those that apply to ordinary proteins. As implemented there is also some constraint on the peptide sequence of the cyclic sequence; for example, libraries may use the sequence SGXX..XXPL to increase the efficiency of circularization of the peptide. SICLOPPS is frequently used with a library of randomized DNA sequence that permits the simultaneous production and screening of large numbers of constructs at once, followed by the recovery of the DNA sequences responsible for the activity of the clone of interest.

Cliotides are a group of related peptides that have been isolated from the heat-stable fraction of Clitoria ternatea (Cliotides) extracts. Cliotides belong to a larger classification of peptides, the cyclotides.

GTx1-15 is a toxin from the Chilean tarantula venom that acts as both a voltage-gated calcium channel blocker and a voltage-gated sodium channel blocker.

<span class="mw-page-title-main">Asparagine endopeptidase</span> Class of enzymes

Asparagine endopeptidase is a proteolytic enzyme from C13 peptidase family which hydrolyses a peptide bond using the thiol group of a cysteine residue as a nucleophile. It is also known as asparaginyl endopeptidase, citvac, proteinase B, hemoglobinase, PRSC1 gene product or LGMN, vicilin peptidohydrolase and bean endopeptidase. In humans it is encoded by the LGMN gene.

A proteolipid is a protein covalently linked to lipid molecules, which can be fatty acids, isoprenoids or sterols. The process of such a linkage is known as protein lipidation, and falls into the wider category of acylation and post-translational modification. Proteolipids are abundant in brain tissue, and are also present in many other animal and plant tissues. They include ghrelin, a peptide hormone associated with feeding. Many proteolipids are composed of proteins covalenently bound to fatty acid chains, often granting them an interface for interacting with biological membranes. They are not to be confused with lipoproteins, a kind of spherical assembly made up of many molecules of lipids and some apolipoproteins.

μ-THTX-Cl6a, also known as Cl6a, is a 33-residue peptide toxin extracted from the venom of the spider Cyriopagopus longipes. The toxin acts as an inhibitor of the tetrodotoxin-sensitive (TTX-S) voltage-gated sodium channel (NaV1.7), thereby causing sustained reduction of NaV1.7 currents.

U7-ctenitoxin-Pn1a (or U7-CNTX-Pn1a for short) is a neurotoxin that blocks TRPV1 channels, and can exhibit analgestic effects. It is naturally found in the venom of Phoneutria nigriventer.

Protoxin-I, also known as ProTx-I, or Beta/omega-theraphotoxin-Tp1a, is a 35-amino-acid peptide neurotoxin extracted from the venom of the tarantula Thrixopelma pruriens. Protoxin-I belongs to the inhibitory cystine knot (ICK) family of peptide toxins, which have been known to potently inhibit voltage-gated ion channels. Protoxin-I selectively blocks low voltage threshold T-type calcium channels, voltage gated sodium channels and the nociceptor cation channel TRPA1. Due to its unique ability to bind to TRPA1, Protoxin-I has been implicated as a valuable pharmacological reagent with potential applications in clinical contexts with regards to pain and inflammation

Cl6b (μ-THTX-Cl6b) is a peptide toxin from the venom of the spider Cyriopagopus longipes. It acts as a sodium channel blocker: Cl6b significantly and persistently reduces currents through the tetrodotoxin-sensitive sodium channels NaV1.2-1.4, NaV1.6, and NaV1.7.

References

  1. ↑ Craik DJ, Daly NL, Bond T, Waine C (December 1999). "Plant cyclotides: A unique family of cyclic and knotted proteins that defines the cyclic cystine knot structural motif". Journal of Molecular Biology. 294 (5): 1327–36. doi:10.1006/jmbi.1999.3383. PMID   10600388.
  2. ↑ Poth AG, Colgrave ML, Lyons RE, Daly NL, Craik DJ (June 2011). "Discovery of an unusual biosynthetic origin for circular proteins in legumes". Proceedings of the National Academy of Sciences of the United States of America. 108 (25): 10127–32. Bibcode:2011PNAS..10810127P. doi: 10.1073/pnas.1103660108 . PMC   3121837 . PMID   21593408.
  3. ↑ Nguyen GK, Zhang S, Nguyen NT, Nguyen PQ, Chiu MS, Hardjojo A, Tam JP (July 2011). "Discovery and characterization of novel cyclotides originated from chimeric precursors consisting of albumin-1 chain a and cyclotide domains in the Fabaceae family". The Journal of Biological Chemistry. 286 (27): 24275–87. doi: 10.1074/jbc.M111.229922 . PMC   3129208 . PMID   21596752.
  4. ↑ Nguyen GK, Lian Y, Pang EW, Nguyen PQ, Tran TD, Tam JP (February 2013). "Discovery of linear cyclotides in monocot plant Panicum laxum of Poaceae family provides new insights into evolution and distribution of cyclotides in plants". The Journal of Biological Chemistry. 288 (5): 3370–80. doi: 10.1074/jbc.M112.415356 . PMC   3561556 . PMID   23195955.
  5. 1 2 3 Dutton JL, Renda RF, Waine C, Clark RJ, Daly NL, Jennings CV, Anderson MA, Craik DJ (November 2004). "Conserved structural and sequence elements implicated in the processing of gene-encoded circular proteins" (PDF). The Journal of Biological Chemistry. 279 (45): 46858–67. doi: 10.1074/jbc.M407421200 . PMID   15328347.
  6. 1 2 3 Jennings C, West J, Waine C, Craik D, Anderson M (September 2001). "Biosynthesis and insecticidal properties of plant cyclotides: the cyclic knotted proteins from Oldenlandia affinis". Proceedings of the National Academy of Sciences of the United States of America. 98 (19): 10614–9. Bibcode:2001PNAS...9810614J. doi: 10.1073/pnas.191366898 . PMC   58514 . PMID   11535828.
  7. ↑ Craik DJ, Daly NL, Mulvenna J, Plan MR, Trabi M (October 2004). "Discovery, structure and biological activities of the cyclotides". Current Protein & Peptide Science. 5 (5): 297–315. doi:10.2174/1389203043379512. PMID   15544527.
  8. ↑ Göransson U, Sjögren M, Svangård E, Claeson P, Bohlin L (August 2004). "Reversible antifouling effect of the cyclotide cycloviolacin O2 against barnacles". Journal of Natural Products. 67 (8): 1287–90. doi:10.1021/np0499719. PMID   15332843.
  9. ↑ Gustafson KR, McKee TC, Bokesch HR (October 2004). "Anti-HIV cyclotides". Current Protein & Peptide Science. 5 (5): 331–40. doi:10.2174/1389203043379468. PMID   15544529.
  10. ↑ 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. Archived from the original on 28 September 2007.
  11. ↑ Gerlach SL, Mondal D (2012). "The bountiful biological activities of cyclotides". Chronicles of Young Scientists. 3 (3): 169–177. doi: 10.4103/2229-5186.99559 .
  12. ↑ Chiche L, Heitz A, Gelly JC, Gracy J, Chau PT, Ha PT, Hernandez JF, Le-Nguyen D (October 2004). "Squash inhibitors: from structural motifs to macrocyclic knottins". Current Protein & Peptide Science. 5 (5): 341–349. doi:10.2174/1389203043379477. PMID   15551519. S2CID   22477930.
  13. ↑ Rosengren KJ, Daly NL, Plan MR, Waine C, Craik DJ (March 2003). "Twists, knots, and rings in proteins. Structural definition of the cyclotide framework". The Journal of Biological Chemistry. 278 (10): 8606–16. doi: 10.1074/jbc.M211147200 . PMID   12482868.
  14. ↑ Ireland DC, Colgrave ML, Nguyencong P, Daly NL, Craik DJ (April 2006). "Discovery and characterization of a linear cyclotide from Viola odorata: implications for the processing of circular proteins". Journal of Molecular Biology. 357 (5): 1522–35. doi:10.1016/j.jmb.2006.01.051. PMID   16488428.
  15. ↑ Simonsen SM, Sando L, Ireland DC, Colgrave ML, Bharathi R, Göransson U, Craik DJ (November 2005). "A continent of plant defense peptide diversity: cyclotides in Australian Hybanthus (Violaceae)". The Plant Cell. 17 (11): 3176–89. doi:10.1105/tpc.105.034678. PMC   1276036 . PMID   16199617.
  16. ↑ Craik DJ (March 2006). "Chemistry. Seamless proteins tie up their loose ends". Science. 311 (5767): 1563–4. doi:10.1126/science.1125248. PMID   16543448. S2CID   82425866.
  17. 1 2 Shafee, Thomas; Harris, Karen; Anderson, Marilyn (1 January 2015). "Biosynthesis of Cyclotides". In Craik, David J. (ed.). Chapter Eight - Biosynthesis of Cyclotides. Plant Cyclotides. Vol. 76. Academic Press. pp. 227–269. doi:10.1016/bs.abr.2015.08.005. ISBN   9780128000304.
  18. ↑ Nguyen GK, Wang S, Qiu Y, Hemu X, Lian Y, Tam JP (September 2014). "Butelase 1 is an Asx-specific ligase enabling peptide macrocyclization and synthesis" (PDF). Nature Chemical Biology. 10 (9): 732–8. doi:10.1038/nchembio.1586. hdl:10220/38787. PMID   25038786.
  19. ↑ Craik DJ, Simonsen S, Daly NL (March 2002). "The cyclotides: novel macrocyclic peptides as scaffolds in drug design". Current Opinion in Drug Discovery & Development. 5 (2): 251–60. PMID   11926131.
  20. ↑ Gunasekera S, Daly NL, Anderson MA, Craik DJ (September 2006). "Chemical synthesis and biosynthesis of the cyclotide family of circular proteins". IUBMB Life. 58 (9): 515–24. doi: 10.1080/15216540600889532 . PMID   17002979.
  21. ↑ Park S, Gunasekera S, Aboye TL, Göransson U (2010). "An Efficient Approach for the Total Synthesis of Cyclotides by Microwave Assisted Fmoc-SPPS". Int. J. Pept. Res. Ther. 16 (3): 167–176. doi:10.1007/s10989-010-9221-0. S2CID   7735199.
  22. ↑ Craik DJ, Cemazar M, Daly NL (March 2006). "The cyclotides and related macrocyclic peptides as scaffolds in drug design". Current Opinion in Drug Discovery & Development. 9 (2): 251–60. PMID   16566295.
  23. ↑ Park S, Strömstedt AA, Göransson U (2014). "Cyclotide structure-activity relationships: qualitative and quantitative approaches linking cytotoxic and anthelmintic activity to the clustering of physicochemical forces". PLOS ONE. 9 (3): e91430. Bibcode:2014PLoSO...991430P. doi: 10.1371/journal.pone.0091430 . PMC   3969350 . PMID   24682019.
  24. 1 2 Werle M, Schmitz T, Huang HL, Wentzel A, Kolmar H, Bernkop-Schnürch A (April 2006). "The potential of cystine-knot microproteins as novel pharmacophoric scaffolds in oral peptide drug delivery". Journal of Drug Targeting. 14 (3): 137–46. doi:10.1080/10611860600648254. PMID   16753827. S2CID   22410195.
  25. ↑ Poth, A. G.; Colgrave, M. L.; Lyons, R. E.; Daly, N. L.; Craik, D. J. (18 May 2011). "Discovery of an unusual biosynthetic origin for circular proteins in legumes". Proceedings of the National Academy of Sciences. 108 (25): 10127–10132. Bibcode:2011PNAS..10810127P. doi: 10.1073/pnas.1103660108 . PMC   3121837 . PMID   21593408.
  26. ↑ Gilding, Edward K.; Jackson, Mark A.; Poth, Aaron G.; Henriques, Sónia Troeira; Prentis, Peter J.; Mahatmanto, Tunjung; Craik, David J. (December 2015). "Gene coevolution and regulation lock cyclic plant defence peptides to their targets" (PDF). New Phytologist. 210 (2): 717–30. doi:10.1111/nph.13789. PMID   26668107.
  27. ↑ Voss-Andreae, J (2005). "Protein Sculptures: Life's Building Blocks Inspire Art". Leonardo. 38: 41–45. doi:10.1162/leon.2005.38.1.41. S2CID   57558522.
  28. ↑ Gran L, Sandberg F, Sletten K (June 2000). "Oldenlandia affinis (R&S) DC. A plant containing uteroactive peptides used in African traditional medicine". Journal of Ethnopharmacology. 70 (3): 197–203. doi:10.1016/S0378-8741(99)00175-0. PMID   10837983.
  29. ↑ Saether O, Craik DJ, Campbell ID, Sletten K, Juul J, Norman DG (April 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.

This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.