Structure-Function Elucidation of a New α-Conotoxin, Lo1a, from Conus longurionis

Lebbe, Eline; Peigneur, Steve; Maiti, Mohitosh; Devi, P. Sujatha; Ravichandran, S.; Lescrinier, Eveline; Ulens, Chris; Waelkens, Etienne; D’Souza, Lisette; Herdewijn, Piet; Tytgat, Jan

doi:10.1074/jbc.m114.556175

Cited by 22 publications

(23 citation statements)

References 75 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The target fraction is concentrated, applied on a cation/anion exchange chromatography column and eluted in accordance with the basicity of the peptide. Reverse phase C18 HPLC with an additional step of rechromatography on the same column for excluding impurities will be used for final purification [ 24 , 25 ].…”

Section: Procedures For Isolating Marine Peptidesmentioning

confidence: 99%

Marine Peptides: Bioactivities and Applications

2015

View full text Add to dashboard Cite

Peptides are important bioactive natural products which are present in many marine species. These marine peptides have high potential nutraceutical and medicinal values because of their broad spectra of bioactivities. Their antimicrobial, antiviral, antitumor, antioxidative, cardioprotective (antihypertensive, antiatherosclerotic and anticoagulant), immunomodulatory, analgesic, anxiolytic anti-diabetic, appetite suppressing and neuroprotective activities have attracted the attention of the pharmaceutical industry, which attempts to design them for use in the treatment or prevention of various diseases. Some marine peptides or their derivatives have high commercial values and had reached the pharmaceutical and nutraceutical markets. A large number of them are already in different phases of the clinical and preclinical pipeline. This review highlights the recent research in marine peptides and the trends and prospects for the future, with special emphasis on nutraceutical and pharmaceutical development into marketed products.

show abstract

Section: Procedures For Isolating Marine Peptidesmentioning

confidence: 99%

Marine Peptides: Bioactivities and Applications

2015

View full text Add to dashboard Cite

show abstract

“…nAChRs are situated in the plasma membranes of certain neurons in the central and peripheral nervous systems [1]. These ligand-gated ion channels are involved in signal transmission, neuronal integration and cell excitability through activation by acetylcholine (ACh) binding [1].…”

Section: Introductionmentioning

confidence: 99%

Effects of C-Terminal Carboxylation on α-Conotoxin LsIA Interactions with Human α7 Nicotinic Acetylcholine Receptor: Molecular Simulation Studies

Wen¹,

Hung²

2019

Marine Drugs

View full text Add to dashboard Cite

α-Conotoxins selectively bind to nicotinic acetylcholine receptors (nAChRs), which are therapeutic targets due to their important role in signaling transmission in excitable cells. A previous experimental study has demonstrated that carboxylation of the C-terminal of α-conotoxin LsIA reduces its potency to inhibit human α7 nAChR relative to naturally amidated LsIA. However, little is known about the contribution of conformational changes in the receptor and interactions, induced by C-terminal amidation/carboxylation of conotoxins, to selective binding to nAChRs, since most conotoxins and some disulfide-rich peptides from other conotoxin subfamilies possess a naturally amidated C-terminal. In this study, we employ homology modeling and molecular dynamics (MD) simulations to propose the determinants for differential interactions between amidated and carboxylated LsIAs with α7 nAChR. Our findings indicate an overall increased number of contacts favored by binding of amidated LsIA versus its carboxylated counterpart. Toxin-receptor pairwise interactions, which may play a role in enhancing the potency of the former, include ARG10-TRP77, LEU141 and CYS17-GLN79 via persistent hydrogen bonds and cation-π interactions, which are weakened in the carboxylated form due to a strong intramolecular salt-bridge formed by ARG10 and carboxylated C-terminus. The binding of amidated LsIA also induces enhanced movements in loop C and the juxtamembrane Cys-loop that are closely associated with receptor function. Additionally, the impacts of binding of LsIA on the overall structure and inter-subunit contacts were examined using inter-residue network analysis, suggesting a clockwise tilting of the α7 C and F loops upon binding to carboxylated LsIA, which is absent for amidated LsIA binding. The predicted molecular mechanism of LsIA binding to the α7 receptor may provide new insights into the important role of the C-terminal in the binding potency of conotoxins at neuronal nAChRs for pharmacological purposes.

show abstract

“…Recently, Giribaldi et al revealed that CIA also blocked the neuronal rat α3β2 nAChR with micromolar potency [43]. As we know, α-4/7-conotoxin was generally regarded as targeting various neuronal nAChRs, however, one α-4/7-conotoxin EI isolated from Conus ermineus was identified as selectively targeting the α/δ interface of the Torpedo muscle-type nAChRs [44], another α-4/7-conotoxin Lo1a has been characterized to differentiate between muscle-type nAChRs and neuronal-type nAChRs, and this conotoxin had a higher affinity at the α/ε interface [45]. Interestingly, αA-conotoxin OIVB with six cysteines isolated from Conus obscurus venoms from Indo-Pacific, exhibited 1800-fold lower affinity for adult muscle nAChRs, and this toxin preferentially bound to the α/γ interface [46].…”

Section: Discussionmentioning

confidence: 99%

Alanine-Scanning Mutagenesis of α-Conotoxin GI Reveals the Residues Crucial for Activity at the Muscle Acetylcholine Receptor

Ning

Ren

et al. 2018

Marine Drugs

View full text Add to dashboard Cite

Recently, the muscle-type nicotinic acetylcholine receptors (nAChRs) have been pursued as a potential target of several diseases, including myogenic disorders, muscle dystrophies and myasthenia gravis, etc. α-conotoxin GI isolated from Conus geographus selectively and potently inhibited the muscle-type nAChRs which can be developed as a tool to study them. Herein, alanine scanning mutagenesis was used to reveal the structure–activity relationship (SAR) between GI and mouse α1β1δε nAChRs. The Pro5, Gly8, Arg9, and Tyr11 were proved to be the critical residues for receptor inhibiting as the alanine (Ala) replacement led to a significant potency loss on mouse α1β1δε nAChR. On the contrary, substituting Asn4, His10 and Ser12 with Ala respectively did not affect its activity. Interestingly, the [E1A] GI analogue exhibited a three-fold potency for mouse α1β1δε nAChR, whereas it obviously decreased potency at rat α9α10 nAChR compared to wildtype GI. Molecular dynamic simulations also suggest that loop2 of GI significantly affects the interaction with α1β1δε nAChR, and Tyr11 of GI is a critical residue binding with three hydrophobic amino acids of the δ subunit, including Leu93, Tyr95 and Leu103. Our research elucidates the interaction of GI and mouse α1β1δε nAChR in detail that will help to develop the novel analogues of GI.

show abstract

Structure-Function Elucidation of a New α-Conotoxin, Lo1a, from Conus longurionis

Cited by 22 publications

References 75 publications

Marine Peptides: Bioactivities and Applications

Marine Peptides: Bioactivities and Applications

Effects of C-Terminal Carboxylation on α-Conotoxin LsIA Interactions with Human α7 Nicotinic Acetylcholine Receptor: Molecular Simulation Studies

Alanine-Scanning Mutagenesis of α-Conotoxin GI Reveals the Residues Crucial for Activity at the Muscle Acetylcholine Receptor

Contact Info

Product

Resources

About