Residues Responsible for the Selectivity of α-Conotoxins for Ac-AChBP or nAChRs

Lin, Bo; Xiang, Shi-Hua; Li, Mengsen

doi:10.3390/md14100173

Cited by 15 publications

(22 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The marine mollusk Aplysia californica expresses a watersoluble protein called AChBP that functions to modulate AChmediated synaptic transmission in this organism (31). X-ray crystallography studies of the AChBP have been used to elucidate binding interactions between ligands and nAChRs (32)(33)(34)(35). Several high-resolution crystal structures have been reported for the AChBP complexed with ␣-Ctxs (36 -39) but not with PeIA.…”

Section: X-ray Crystallography Of Peia Complexed With Aplysia Califormentioning

confidence: 99%

Molecular determinants of α-conotoxin potency for inhibition of human and rat α6β4 nicotinic acetylcholine receptors

Hone¹,

Talley

Bobango

et al. 2018

Journal of Biological Chemistry

View full text Add to dashboard Cite

Edited by Wolfgang PetiNicotinic acetylcholine receptors (nAChRs) containing ␣6 and ␤4 subunits are expressed by dorsal root ganglion neurons and have been implicated in neuropathic pain. Rodent models are often used to evaluate the efficacy of analgesic compounds, but species differences may affect the activity of some nAChR ligands. A previous candidate ␣-conotoxin-based therapeutic yielded promising results in rodent models, but failed in human clinical trials, emphasizing the importance of understanding species differences in ligand activity. Here, we show that human and rat ␣6/␣3␤4 nAChRs expressed in Xenopus laevis oocytes exhibit differential sensitivity to ␣-conotoxins. Sequence homology comparisons of human and rat ␣6␤4 nAChR subunits indicated that ␣6 residues forming the ligand-binding pocket are highly conserved between the two species, but several residues of ␤4 differed, including a Leu-Gln difference at position 119. X-ray crystallography of ␣-conotoxin PeIA complexed with the Aplysia californica acetylcholine-binding protein (AChBP) revealed that binding of PeIA orients Pro 13 in close proximity to residue 119 of the AChBP complementary subunit. Sitedirected mutagenesis studies revealed that Leu 119 of human ␤4 contributes to higher sensitivity of human ␣6/␣3␤4 nAChRs to ␣-conotoxins, and structure-activity studies indicated that PeIA Pro 13 is critical for high potency. Human and rat ␣6/␣3␤4 nAChRs displayed differential sensitivities to perturbations of the interaction between PeIA Pro 13 and residue 119 of the ␤4 subunit. These results highlight the potential significance of species differences in ␣6␤4 nAChR pharmacology that should be taken into consideration when evaluating the activity of candidate human therapeutics in rodent models.Nicotinic acetylcholine receptors (nAChRs) 5 are ligandgated ion channels formed by the pentameric assembly of individual subunits. There are 16 genes in mammals that encode these subunits and are represented by the Greek symbols ␣1-␣7, ␣9, ␣10, ␤1-␤4, ␦, ⑀, and ␥ (1). nAChRs are expressed by neurons in both the central and peripheral nervous systems and are involved in diverse physiological processes (2), including fast synaptic transmission (3), the modulation of neurotransmitter release (4 -10), and numerous immunological processes (11,12).Native nAChRs containing the ␣6 subunit are broadly classified into two subtype categories: those that contain the ␤2 subunit and those that contain the ␤4 subunit. The ␣6␤2* subtype (the asterisk denotes the potential presence of additional subunits in native receptors) has a limited distribution profile in the nervous system but is abundantly expressed in certain regions of the brain and spinal cord (13)(14)(15)(16)(17)(18)(19). The ␣6␤4* subtype probably has an even more restricted expression profile. Functional evidence for ␣6␤4* nAChR expression in sensory neurons of rat and mouse dorsal root ganglia (DRG) has been demonstrated (20, 21), although their functional role in these cells is mostly unknown.DRG contain neuron...

show abstract

Section: X-ray Crystallography Of Peia Complexed With Aplysia Califormentioning

confidence: 99%

Molecular determinants of α-conotoxin potency for inhibition of human and rat α6β4 nicotinic acetylcholine receptors

Hone¹,

Talley

Bobango

et al. 2018

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…The two other possible isomers are the ribbon (C I –C IV and C II –C III ) and bead (C I –C II and C III –C IV ) (Millard et al, ; Muttenthaler et al, ). Comprehensive reviews of α‐conotoxins and their pharmacological activities at muscle and neuronal nAChRs subtypes have been published (Azam and McIntosh, ; Muttenthaler et al, ; Lebbe et al, ; Lin et al, ).…”

Section: α‐Conotoxins a Class Of Conotoxins Active At Nachrsmentioning

confidence: 99%

“…Since the time when its crystal structure was determined, it has proved to be a valuable tool to study conotoxin‐nAChR interactions. Co‐crystal structures of α‐conotoxins in complex with Ac‐AChBP have been reported for PnIA[A10L,D14K] (PDB code 2BR8), TxIA[A10L] (PDB code 2UZ6), ImI (PDB code 2C9T), BuIA (PDB code 4EZ1) and GIC (PDB code 5CO5) (Lin et al, ).…”

Section: Molecular Determinants In the Agonist Binding Loops Of Humanmentioning

confidence: 99%

α‐Conotoxins active at α3‐containing nicotinic acetylcholine receptors and their molecular determinants for selective inhibition

Cuny

Tae

et al. 2017

British J Pharmacology

View full text Add to dashboard Cite

show abstract

“…All the modelling, docking and simulations were performed in Discovery Studio Client 4.0 (Accelrys, San Diego, CA, USA). The molecular models of extracellular ligand-binding domains of the human nAChRs (such as α3β2) were generated based on the template of Ac-AChBP structure using the homology modelling program Modeler version 9.0 [ 39 ]. The structure of α-conotoxin ImI (PDB: P50983) was downloaded from the public PDB database.…”

Section: Methodsmentioning

confidence: 99%

Screening and Validation of Highly-Efficient Insecticidal Conotoxins from a Transcriptome-Based Dataset of Chinese Tubular Cone Snail

Gao

Peng

Lin

et al. 2017

Toxins

Self Cite

View full text Add to dashboard Cite

Most previous studies have focused on analgesic and anti-cancer activities for the conotoxins identified from piscivorous and molluscivorous cone snails, but little attention has been devoted to insecticidal activity of conotoxins from the dominant vermivorous species. As a representative vermivorous cone snail, the Chinese tubular cone snail (Conus betulinus) is the dominant Conus species inhabiting the South China Sea. We sequenced related venom transcriptomes from C. betulinus using both the next-generation sequencing and traditional Sanger sequencing technologies, and a comprehensive library of 215 conotoxin transcripts was constructed. In our current study, six conotoxins with potential insecticidal activity were screened out from our conotoxin library by homologous search with a reported positive control (alpha-conotoxin ImI from C. imperialis) as the query. Subsequently, these conotoxins were synthesized by chemical solid-phase and oxidative folding for further insecticidal activity validation, such as MTT assay, insect bioassay and homology modeling. The final results proved insecticidal activities of our achieved six conotoxins from the transcriptome-based dataset. Interestingly, two of them presented a lot of high insecticidal activity, which supports their usefulness for a trial as insecticides in field investigations. In summary, our present work provides a good example for high throughput development of biological insecticides on basis of the accumulated genomic resources.

show abstract

Residues Responsible for the Selectivity of α-Conotoxins for Ac-AChBP or nAChRs

Cited by 15 publications

References 57 publications

Molecular determinants of α-conotoxin potency for inhibition of human and rat α6β4 nicotinic acetylcholine receptors

Molecular determinants of α-conotoxin potency for inhibition of human and rat α6β4 nicotinic acetylcholine receptors

α‐Conotoxins active at α3‐containing nicotinic acetylcholine receptors and their molecular determinants for selective inhibition

Screening and Validation of Highly-Efficient Insecticidal Conotoxins from a Transcriptome-Based Dataset of Chinese Tubular Cone Snail

Contact Info

Product

Resources

About