scholarly journals Fish-hunting cone snail venoms are a rich source of minimized ligands of the vertebrate insulin receptor

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Peter Ahorukomeye ◽  
Maria M Disotuar ◽  
Joanna Gajewiak ◽  
Santhosh Karanth ◽  
Maren Watkins ◽  
...  
Keyword(s):  
Insulin Receptor ◽  
Rich Source ◽  
Cone Snail ◽  
Lower Blood Glucose ◽  
Human Insulin Receptor ◽  
Novel Drugs ◽  
Lower Blood ◽  
Treatment Of Diabetes ◽  
Cone Snails ◽  
Insight Into

The fish-hunting marine cone snail Conus geographus uses a specialized venom insulin to induce hypoglycemic shock in its prey. We recently showed that this venom insulin, Con-Ins G1, has unique characteristics relevant to the design of new insulin therapeutics. Here, we show that fish-hunting cone snails provide a rich source of minimized ligands of the vertebrate insulin receptor. Insulins from C. geographus, Conus tulipa and Conus kinoshitai exhibit diverse sequences, yet all bind to and activate the human insulin receptor. Molecular dynamics reveal unique modes of action that are distinct from any other insulins known in nature. When tested in zebrafish and mice, venom insulins significantly lower blood glucose in the streptozotocin-induced model of diabetes. Our findings suggest that cone snails have evolved diverse strategies to activate the vertebrate insulin receptor and provide unique insight into the design of novel drugs for the treatment of diabetes.

scholarly journals Ero1-Mediated Reoxidation of Protein Disulfide Isomerase Accelerates the Folding of Cone Snail Toxins

2018 ◽  
Vol 19 (11) ◽  
pp. 3418 ◽  
Author(s):  
Henrik O’Brien ◽  
Shingo Kanemura ◽  
Masaki Okumura ◽  
Robert Baskin ◽  
Pradip Bandyopadhyay ◽  
...  
Keyword(s):  
Protein Disulfide Isomerase ◽  
Venom Gland ◽  
Cone Snail ◽  
Disulfide Isomerase ◽  
Folding Rates ◽  
Cone Snails ◽  
And Function ◽  
Protein Disulfide ◽  
Insight Into

Disulfide-rich peptides are highly abundant in nature and their study has provided fascinating insight into protein folding, structure and function. Venomous cone snails belong to a group of organisms that express one of the largest sets of disulfide-rich peptides (conotoxins) found in nature. The diversity of structural scaffolds found for conotoxins suggests that specialized molecular adaptations have evolved to ensure their efficient folding and secretion. We recently showed that canonical protein disulfide isomerase (PDI) and a conotoxin-specific PDI (csPDI) are ubiquitously expressed in the venom gland of cone snails and play a major role in conotoxin folding. Here, we identify cone snail endoplasmic reticulum oxidoreductin-1 (Conus Ero1) and investigate its role in the oxidative folding of conotoxins through reoxidation of cone snail PDI and csPDI. We show that Conus Ero1 preferentially reoxidizes PDI over csPDI, suggesting that the reoxidation of csPDI may rely on an Ero1-independent molecular pathway. Despite the preferential reoxidation of PDI over csPDI, the combinatorial effect of Ero1 and csPDI provides higher folding yields than Ero1 and PDI. We further demonstrate that the highest in vitro folding rates of two model conotoxins are achieved when all three enzymes are present, indicating that these enzymes may act synergistically. Our findings provide new insight into the generation of one of the most diverse classes of disulfide-rich peptides and may improve current in vitro approaches for the production of venom peptides for pharmacological studies.

scholarly journals REVIEW ON MANAGEMENT PREVENTION AND TREATMENT OF DIABETES MELLITUS

2019 ◽  
Vol 7 (2) ◽  
pp. 56-62
Author(s):  
Nagoba Shivappa N ◽  
Sugave Ramling V ◽  
Ningule Ganesh M ◽  
Patil Pooja Y
Keyword(s):  
Diabetes Mellitus ◽  
Developed Countries ◽  
Lower Blood Glucose ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Lower Blood ◽  
Treatment Of Diabetes ◽  
Toxicity Of Drugs ◽  
Oral Hypoglycemic Drugs

Diabetes mellitus is the third leading cause of death (after heart disease and cancer) in many developed countries it affect about 6-8% of general population. The complication occurs in diabetes mellitus affect the eye, kidney and nervous system. Diabetes is major cause of blindness, renal failure and heart attack. And another is diabetes insipidus. India is the diabetes capital of the world. In India 50 million peoples suffering from type-2 diabetes. This country has major challenge & burden of economic condition to face. Because diabetes mellitus insulin therapy have higher cost & demand is more. But medical experts that timely detection and right management can go a long way in helping patients lead a normal life. That required to more demanding new drug that have need to develop more bioavailability and less toxicity of drugs. Oral hypoglycemic drugs these drugs lower blood glucose levels and are effective orally. Some natural antidiabetic drugs used in treatment of diabetes mellitus, gymnema, pterocarpus, Jamun, bitter guard etc.  

scholarly journals Visualization of Insulin Receptor Activation by a Novel Insulin Analog with Elongated A Chain and Truncated B Chain

2021 ◽  
Author(s):  
Xiaochun Xiong ◽  
Alan Blakely ◽  
Jin Hwan Kim ◽  
John Menting ◽  
Ingmar Schafer ◽  
...  
Keyword(s):  
Insulin Receptor ◽  
Receptor Activation ◽  
Structural Features ◽  
Biochemical Properties ◽  
Asymmetric Structure ◽  
Binding Modes ◽  
Cone Snail ◽  
Human Insulin Receptor ◽  
A Chain ◽  
Receptor Conformation

Abstract Cone snail venoms contain a wide variety of bioactive peptides, including insulin-like molecules with distinct structural features, binding modes, and biochemical properties. Here, we report a fully active humanized cone snail venom insulin with an elongated A chain and a truncated B chain, and use cryo-electron microscopy and protein engineering to elucidate its interactions with the human insulin receptor ectodomain. We reveal how an extended A chain can compensate for deletion of B-chain residues, which are essential for activity of native insulin but also compromise therapeutic utility by delaying the onset action, suggesting approaches to develop improved therapeutic insulins. Curiously, a receptor conformation present in low abundance adopts a highly asymmetric structure that displays novel coordination of a single humanized venom insulin using elements from both of the previously characterized site 1 and site 2 interactions.

scholarly journals Author response: Fish-hunting cone snail venoms are a rich source of minimized ligands of the vertebrate insulin receptor

2018 ◽  
Author(s):  
Peter Ahorukomeye ◽  
Maria M Disotuar ◽  
Joanna Gajewiak ◽  
Santhosh Karanth ◽  
Maren Watkins ◽  
...  
Keyword(s):  
Insulin Receptor ◽  
Rich Source ◽  
Author Response ◽  
Cone Snail

scholarly journals Structure-based survey of ligand binding in the human insulin receptor

2021 ◽  
Author(s):  
Judith Klein-Seetharaman ◽  
Whitney Vizgaudis ◽  
Lokender Kumar
Keyword(s):  
Ligand Binding ◽  
Insulin Receptor ◽  
Human Insulin ◽  
Nutrient Balance ◽  
Docking Study ◽  
Human Insulin Receptor ◽  
Receptor Pharmacology ◽  
Entire Sequence ◽  
Treatment Of Diabetes ◽  
Structural Insights

The insulin receptor is a membrane protein responsible for regulation of nutrient balance and therefore an attractive target in the treatment of diabetes and metabolic syndrome. Pharmacology of the insulin receptor involves two distinct mechanisms, (1) activation of the receptor by insulin mimetics that bind in the extracellular domain and (2) inhibition of the receptor tyrosine kinase enzymatic activity in the cytoplasmic domain. While a complete structural picture of the full-length receptor comprising the entire sequence covering extracellular, transmembrane, juxtamembrane and cytoplasmic domains is still elusive, recent progress through cryoelectron microscopy has made it possible to describe the initial insulin ligand binding events at atomistic detail. We utilize this opportunity to obtain structural insights into the pharmacology of the insulin receptor. To this end, we conducted a comprehensive docking study of known ligands to the new structures of the receptor. Through this approach, we provide an in-depth, structure-based review of human insulin receptor pharmacology in light of the new structures.

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