Abstract:Defensins are a well-characterised group of small, disulphide-rich, cationic peptides that are produced by essentially all eukaryotes and are highly diverse in their sequences and structures. Most display broad range antimicrobial activity at low micromolar concentrations, whereas others have other diverse roles, including cell signalling (e.g. immune cell recruitment, self/non-self-recognition), ion channel perturbation, toxic functions, and enzyme inhibition. The defensins consist of two superfamilies, each … Show more
“…6B). It is composed of one α-helix and three antiparallel β-strands 27 . The CSαβ motif was first characterized in charybdotoxin 28, 29 .…”
Section: Discussionmentioning
confidence: 99%
“…However, in defensins, there are two types of precursor structure organization. The plant C8 class II defensins have a similar three domain organization as lybatides and thionins, whereas the plant class I defensin precursors do not contain the C-tail domain 27 .Figure 7Precursor gene structure organization of lybatides. ( A ) Predicted precursor structure of lybatides based on homologous sequences.…”
1Cysteine-rich peptides (CRPs) of 2-6 kDa are generally thermally and proteolytically stable because of their multiple cross-bracing disulfide bonds. Here, we report the discovery and characterization of two novel cystine-stapled CRPs, designated lybatide 1 and 2 (lyba1 and lyba2), from the cortex of Lycium barbarum root. Lybatides, 32 to 33 amino acids in length, are hyperstable and display a novel disulfide connectivity with a cysteine motif of C-C-C-C-CC-CC which contains two pairs of adjacent cysteines (-CC-CC). X-ray structure analysis revealed the presence of a single cystine-stabilized (α + π)-helix in lyba2, a rare feature of CRPs. Together, our results suggest that lybatides, one of the smallest four-disulfideconstrained plant CRPs, is a new family of CRPs. Additionally, this study provides new insights into the molecular diversity of plant cysteine-rich peptides and the unusual lybatide scaffold could be developed as a useful template for peptide engineering and therapeutic development.Lycium barbarum, belonging to the Solanaceae family, is a deciduous shrub native to southeastern China 1 . It is the plant that produces the popular herb wolfberries or goji berries. However, the cortex of L. barbarum root ( or DiGuPi in Chinese) is also commonly used as a traditional Chinese medicine for treating chronic low-grade fever, cough, hemoptysis and hematuria, diabetes mellitus and hypertension 1 . A diverse group of secondary metabolites has been isolated from the cortex of L. barbarum root, including alkaloids, flavonoids and flavone glycosides. In addition, small cyclic peptides, namely licyumins A-D, with molecular weights <1 kDa, have been shown to inhibit renin and angiotensin-converting enzymes 2 . However, no bioactive peptides >2 kDa have been reported.Bioactive compounds from medicinal plants have been a source of inspiring structures for drug discovery. A majority of studies focuses on small molecules and secondary metabolites, with few studies focusing on peptides 3,4 . Even in studies relating to identifying peptides from plants, the focus is largely on small cyclic peptides. This bias is attributed to a general perception that peptides >2 kDa are unstable and readily denatured during a decoction preparation or in the gastrointestinal tract after ingestion. This is generally true for large peptides and proteins with molecular weight >8 kDa. However, cysteine-rich peptides (CRPs) with a molecular range of 2-6 kDa and 3-5 disulfide bonds are tolerant to thermal, chemical and proteolytic degradation 5 . As a group, CRPs in this defined chemical space have great potential as a source of leads and inspiration for developing useful drugs from medicinal plants 6,7 . Structurally, plant CRPs within the chemical space of 2-6 kDa can be arbitrarily classified into two major groups (Fig. 1). They are the cystine-stabilized α-helical (CSα) peptides and cystine-stabilized β-peptides. The CSα peptides can be found in plant CRPs >40 residues such as plant defensins and plant thionins. Cystine-stabilized β-peptid...
“…6B). It is composed of one α-helix and three antiparallel β-strands 27 . The CSαβ motif was first characterized in charybdotoxin 28, 29 .…”
Section: Discussionmentioning
confidence: 99%
“…However, in defensins, there are two types of precursor structure organization. The plant C8 class II defensins have a similar three domain organization as lybatides and thionins, whereas the plant class I defensin precursors do not contain the C-tail domain 27 .Figure 7Precursor gene structure organization of lybatides. ( A ) Predicted precursor structure of lybatides based on homologous sequences.…”
1Cysteine-rich peptides (CRPs) of 2-6 kDa are generally thermally and proteolytically stable because of their multiple cross-bracing disulfide bonds. Here, we report the discovery and characterization of two novel cystine-stapled CRPs, designated lybatide 1 and 2 (lyba1 and lyba2), from the cortex of Lycium barbarum root. Lybatides, 32 to 33 amino acids in length, are hyperstable and display a novel disulfide connectivity with a cysteine motif of C-C-C-C-CC-CC which contains two pairs of adjacent cysteines (-CC-CC). X-ray structure analysis revealed the presence of a single cystine-stabilized (α + π)-helix in lyba2, a rare feature of CRPs. Together, our results suggest that lybatides, one of the smallest four-disulfideconstrained plant CRPs, is a new family of CRPs. Additionally, this study provides new insights into the molecular diversity of plant cysteine-rich peptides and the unusual lybatide scaffold could be developed as a useful template for peptide engineering and therapeutic development.Lycium barbarum, belonging to the Solanaceae family, is a deciduous shrub native to southeastern China 1 . It is the plant that produces the popular herb wolfberries or goji berries. However, the cortex of L. barbarum root ( or DiGuPi in Chinese) is also commonly used as a traditional Chinese medicine for treating chronic low-grade fever, cough, hemoptysis and hematuria, diabetes mellitus and hypertension 1 . A diverse group of secondary metabolites has been isolated from the cortex of L. barbarum root, including alkaloids, flavonoids and flavone glycosides. In addition, small cyclic peptides, namely licyumins A-D, with molecular weights <1 kDa, have been shown to inhibit renin and angiotensin-converting enzymes 2 . However, no bioactive peptides >2 kDa have been reported.Bioactive compounds from medicinal plants have been a source of inspiring structures for drug discovery. A majority of studies focuses on small molecules and secondary metabolites, with few studies focusing on peptides 3,4 . Even in studies relating to identifying peptides from plants, the focus is largely on small cyclic peptides. This bias is attributed to a general perception that peptides >2 kDa are unstable and readily denatured during a decoction preparation or in the gastrointestinal tract after ingestion. This is generally true for large peptides and proteins with molecular weight >8 kDa. However, cysteine-rich peptides (CRPs) with a molecular range of 2-6 kDa and 3-5 disulfide bonds are tolerant to thermal, chemical and proteolytic degradation 5 . As a group, CRPs in this defined chemical space have great potential as a source of leads and inspiration for developing useful drugs from medicinal plants 6,7 . Structurally, plant CRPs within the chemical space of 2-6 kDa can be arbitrarily classified into two major groups (Fig. 1). They are the cystine-stabilized α-helical (CSα) peptides and cystine-stabilized β-peptides. The CSα peptides can be found in plant CRPs >40 residues such as plant defensins and plant thionins. Cystine-stabilized β-peptid...
“…Two disulfide bonds connect the C-terminal β-sheet and the α-helix and the third connects the N-terminal loop with the second β-sheet. Similar to peptides from plants or fungi they are hence classified as cis -defensins as opposed to trans -defensins found within vertebrate species (Shafee et al, 2017). The tight arrangement of secondary structural elements is reflected in high stability against heat or proteases.…”
Section: Structure-activity Relationships Of Insect Defensinsmentioning
confidence: 99%
“…The tight arrangement of secondary structural elements is reflected in high stability against heat or proteases. Accordingly, this structural topology is known as cysteine-stabilized αβ motif (CSαβ) and is common among defensin peptides across different organisms, from plants to invertebrates to vertebrates (Dias Rde and Franco, 2015; Tarr, 2016; Shafee et al, 2017). Although all insect defensins share this common structural motif their primary sequence (Figure 1A) as well as their spectrum of antimicrobial activity varies considerably (Table 1).…”
Section: Structure-activity Relationships Of Insect Defensinsmentioning
confidence: 99%
“…This includes for example antimicrobial peptides (AMP) that represent an important part of the organism's defense machinery or peptide toxins as part of venom cocktails (Brogden et al, 2003; Favreau et al, 2006; Aili et al, 2014). AMPs are a diverse class of naturally occurring compounds that have been identified in a variety of organisms, from invertebrates to vertebrates including humans (Shafee et al, 2017). In particular insects are known for their immune system that has evolved a complex arrangement of constitutive and inducible AMPs that are used to defend against invading microorganisms (Kingsolver et al, 2013) and allow a symbiotic lifestyle with various microbes (Douglas, 2015).…”
Insects make up the largest and most diverse group of organisms on earth with several million species to exist in total. Considering the sheer number of insect species and the vast variety of ways they interact with their environment through chemistry, it is clear that they have significant potential as a source of new lead molecules. They have adapted to a range of ecological habitats and exhibit a symbiotic lifestyle with various microbes such as bacteria and fungi. Accordingly, numerous antimicrobial compounds have been identified including for example defensin peptides. Insect defensins were found to have broad-spectrum activity against various gram-positive/negative bacteria as well as fungi. They exhibit a unique structural topology involving the complex arrangement of three disulfide bonds as well as an alpha helix and beta sheets, which is known as cysteine-stabilized αβ motif. Their stability and amenability to peptide engineering make them promising candidates for the development of novel antibiotics lead molecules. This review highlights the current knowledge regarding the structure-activity relationships of insect defensin peptides and provides basis for future studies focusing on the rational design of novel cysteine-rich antimicrobial peptides.
Defensins are innate immune molecules that upon recognition of specific phospholipids can disrupt microbial membranes by forming oligomeric assemblies. Structures of two related plant defensins, NaD1 and NsD7, bound to phosphatidylinositol 4,5-bisphosphate (PIP ) and phosphatidic acid (PA), respectively, revealed striking differences in their oligomeric topologies. To understand how NsD7 binds different phospholipids and rationalize the different topologies, we determined the structure of an NsD7-PIP complex. This structure reveals fundamental differences in phospholipid binding compared to NsD7-PA, and an oligomeric topology nearly identical to the previously determined NaD1-PIP complex, establishing that the PIP fibril topology is conserved between NaD1 and NsD7. Our findings highlight the remarkable ability of defensins to bind different types of phospholipids to form oligomeric fibrils with diverse topologies.
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