A Disulfide Stabilized β-Sandwich Defines the Structure of a New Cysteine Framework M-Superfamily Conotoxin

Kancherla, Aswani K.; Meesala, Srinu; Jorwal, Pooja; Ramasamy, P.; Sikdar, Sujit Kumar; Sarma, Siddhartha P.

doi:10.1021/acschembio.5b00226

Cited by 6 publications

(7 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contrast to the two other fold I toxins, the connectivities of the first two disulfide bonds of CcTx are exchanged, i.e., CcTx has the connectivity 1−3, 2−5, and 4−6, and the other toxins have the connectivity 1−5, 2−3, and 4−6. The same connectivity was discovered for the four cysteine framework XXVII Mo3964, 125 which displays the new fold O (Figure 30). Fold I does not display any regular secondary structure, whereas fold O comprises two β-sheets, one made of three β-strands and the other of two β-strands.…”

Section: Structures Of Framework With Six Cysteinessupporting

confidence: 69%

“…Conus monile. 125 The expressed folded peptide has a βsandwich structure that is stabilized by intersheet cross disulfide bonds. This toxin inhibited voltage-gated potassium channels in dorsal root ganglion (DRG) neurons.…”

Section: Framework XXVI C−c−c−c−cc−ccmentioning

confidence: 99%

“…The sole member of framework XXVIII is κ-Mo3964 (Figure ) from Conus monile . The expressed folded peptide has a β-sandwich structure that is stabilized by intersheet cross disulfide bonds.…”

Section: Integrated Venomicsmentioning

confidence: 99%

See 2 more Smart Citations

Conotoxins: Chemistry and Biology

et al. 2019

View full text Add to dashboard Cite

The venom of the marine predatory cone snails (genus Conus) has evolved for prey capture and defense, providing the basis for survival and rapid diversification of the now estimated 750+ species. A typical Conus venom contains hundreds to thousands of bioactive peptides known as conotoxins. These mostly disulfide-rich and well-structured peptides act on a wide range of targets such as ion channels, G protein-coupled receptors, transporters, and enzymes. Conotoxins are of interest to neuroscientists as well as drug developers due to their exquisite potency and selectivity, not just against prey but also mammalian targets, thereby providing a rich source of molecular probes and therapeutic leads. The rise of integrated venomics has accelerated conotoxin discovery with now well over 10,000 conotoxin sequences published. However, their structural and pharmacological characterization lags considerably behind. In this review, we highlight the diversity of new conotoxins uncovered since 2014, their three-dimensional structures and folds, novel chemical approaches to their syntheses, and their value as pharmacological tools to unravel complex biology. Additionally, we discuss challenges and future directions for the field.

show abstract

Section: Structures Of Framework With Six Cysteinessupporting

confidence: 69%

Section: Framework XXVI C−c−c−c−cc−ccmentioning

confidence: 99%

See 1 more Smart Citation

Conotoxins: Chemistry and Biology

et al. 2019

View full text Add to dashboard Cite

show abstract

“…8 In general, disulfide-rich peptides have enhanced stability compared to linear disulfide-poor peptides and are thus thought to be excellent drug leads. [21][22] Additionally, they have a wide range of therapeutically interesting activities. There are now several examples of native and engineered disulfide-rich peptides that have high stability and potent activities in vitro and in vivo.…”

Section: Discussionmentioning

confidence: 99%

Calcium-Mediated Allostery of the EGF Fold

et al. 2018

View full text Add to dashboard Cite

The epidermal growth factor (EGF)-like domain is one of the most abundant disulfide-containing domains in nature and is involved in many cellular processes critical to life. Although many EGF-like domains participate in calcium-dependent functions by responding to the local calcium concentration, little is known about how this responsiveness is programmed at the molecular level. Here, we reveal the structural and environmental determinants underpinning the folding of a synthetic analogue of the EGF-A domain (from the low-density lipoprotein receptor). We show that calcium sensitivity is enabled by an allosteric folding pathway, in which calcium binding is connected to the peptide core through local inter-residue interactions. In the absence of calcium, the fold favors disorder because the inherently weak core is insufficient to stabilize the active form, resulting in substantial loss in activity of 2 orders of magnitude. The EGF-A fold, which can freely transition between active and disordered states, is volatile, and we found it to be intolerant of mutations, unlike other disulfide-rich peptides that have been used as stabilizing frameworks. This volatility is beneficial for modularity/plasticity and appears to have evolved for such a purpose, allowing cellular pathways to sense and respond to environmental cues.

show abstract

“…Conotoxins with a similar cysteine network usually carry a similar signal sequence. So far, these distinct cysteine frameworks have been described in conotoxins and they are often considered to be associated with particular pharmacological families [ 21 , 28 , 29 , 31 , 32 ].…”

Section: Introductionmentioning

confidence: 99%

A Transcriptomic Survey of Ion Channel-Based Conotoxins in the Chinese Tubular Cone Snail (Conus betulinus)

Huang

Peng

et al. 2017

Marine Drugs

View full text Add to dashboard Cite

Conotoxins in the venom of cone snails (Conus spp.) are a mixture of active peptides that work as blockers, agonists, antagonists, or inactivators of various ion channels. Recently we reported a high-throughput method to identify 215 conotoxin transcripts from the Chinese tubular cone snail, C. betulinus. Here, based on the previous datasets of four transcriptomes from three venom ducts and one venom bulb, we explored ion channel-based conotoxins and predicted their related ion channel receptors. Homologous analysis was also performed for the most abundant ion channel protein, voltage-gated potassium (Kv; with Kv1.1 as the representative), and the most studied ion channel receptor, nicotinic acetylcholine receptor (nAChR; with α2-nAChR as the representative), in different animals. Our transcriptomic survey demonstrated that ion channel-based conotoxins and related ion channel proteins/receptors transcribe differentially between the venom duct and the venom bulb. In addition, we observed that putative κ-conotoxins were the most common conotoxins with the highest transcription levels in the examined C. betulinus. Furthermore, Kv1.1 and α2-nAChR were conserved in their functional domains of deduced protein sequences, suggesting similar effects of conotoxins via the ion channels in various species, including human beings. In a word, our present work suggests a high-throughput way to develop conotoxins as potential drugs for treatment of ion channel-associated human diseases.

show abstract

A Disulfide Stabilized β-Sandwich Defines the Structure of a New Cysteine Framework M-Superfamily Conotoxin

Cited by 6 publications

References 61 publications

Conotoxins: Chemistry and Biology

Conotoxins: Chemistry and Biology

Calcium-Mediated Allostery of the EGF Fold

A Transcriptomic Survey of Ion Channel-Based Conotoxins in the Chinese Tubular Cone Snail (Conus betulinus)

Contact Info

Product

Resources

About