Structure-Function of Neuronal Nicotinic Acetylcholine Receptor Inhibitors Derived From Natural Toxins

Ho, Thao N. T.; Abraham, Nikita; Lewis, Richard J.

doi:10.3389/fnins.2020.609005

Cited by 49 publications

(24 citation statements)

References 151 publications

(230 reference statements)

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“…The remaining binding interfaces show reduced ligand densities that could arise from an influence of crystal packing on AusIA pharmacology. The C-loop was displaced outward by 10.3 ± 0.34 Å in the occupied binding interface, which is comparable to previous co-crystal structures of bound α-conotoxins (based on the measurement between Cys187 C α atom in the complex with HEPES/ Ls -AChBP structure) 18 , while the C-loops of other binding interfaces remained in a closed conformation (Fig. 1 b).…”

Section: Resultssupporting

confidence: 88%

Rigidity of loop 1 contributes to equipotency of globular and ribbon isomers of α-conotoxin AusIA

Abraham

Lewis

2021

Sci Rep

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Abstractα-Conotoxins are small disulfide-rich peptides targeting nicotinic acetylcholine receptors (nAChRs) characterised by a CICII-Xm-CIII-Xn-CIV framework that invariably adopt the native globular conformations which is typically most potent. α-Conotoxins are divided into several structural subgroups based on the number of residues within the two loops braced by the disulfide bonds (m/n), with the 4/7 and 4/3 subgroups dominating. AusIA is a relatively rare α5/5-conotoxin isolated from the venom of Conus australis. Surprisingly, the ribbon isomer displayed equipotency to the wild-type globular AusIA at human α7-containing nAChR. To understand the molecular basis for equipotency, we determined the co-crystal structures of both isomers at Lymnea stagnalis acetylcholine binding protein. The additional residue in the first loop of AusIA was found to be a critical determinant of equipotency, with 11-fold and 86-fold shifts in potency in favour of globular AusIA over ribbon AusIA observed following deletion of Ala4 or Arg5, respectively. This divergence in the potency between globular AusIA and ribbon AusIA was further enhanced upon truncation of the non-conserved Val at the C-termini. Conversely, equipotency could be replicated in LsIA and TxIA [A10L] following insertion of an Ala in the first loop. These findings provide a new understanding of the role the first loop in ribbon and globular α-conotoxins can play in directing α-conotoxin nAChR pharmacology.

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Section: Resultssupporting

confidence: 88%

Rigidity of loop 1 contributes to equipotency of globular and ribbon isomers of α-conotoxin AusIA

Abraham

Lewis

2021

Sci Rep

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“…The neural nAChR is one of the most concerned ion channels and membrane proteins. So far, researchers have cloned 14 different nAChR subunits have been identified in vertebrates, including α1–α10, β1–β4 [ 4 , 5 ], which can co-assemble to form multiple functional heteropentamers or homopentamers. The α3β2 nAChR is one of the important subtypes which is mainly distributed in the dorsal root ganglion and spinal cord [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Characterization of an α 4/7-Conotoxin LvIF from Conus lividus That Selectively Blocks α3β2 Nicotinic Acetylcholine Receptor

Guo

Zhu

et al. 2021

Marine Drugs

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Nicotinic acetylcholine receptor (nAChR), a member of pentameric ligand-gated ion channel transmembrane protein composed of five subunits, is widely distributed in the central and peripheral nervous system. The nAChRs are associated with various neurological diseases, including schizophrenia, Alzheimer’s disease, Parkinson’s disease, epilepsy and neuralgia. Receptors containing the α3 subunit are associated with analgesia, generating our interest in their role in pharmacological studies. In this study, α-conotoxin (α-CTx) LvIF was identified as a 16 amino acid peptide using a genomic DNA clone of Conus lividus (C. lividus). The mature LvIF with natural structure was synthesized by a two-step oxidation method. The blocking potency of α-CTx lvIF on nAChR was detected by a two-electrode voltage clamp. Our results showed that α-CTx LvIF was highly potent against rα3β2 and rα6/α3β2β3 nAChR subtypes, The half-maximal inhibitory concentration (IC50) values of α-CTx LvIF against rα3β2 and rα6/α3β2β3 nAChRs expressed in Xenopus oocytes were 8.9 nM and 14.4 nM, respectively. Furthermore, α-CTx LvIF exhibited no obvious inhibition on other nAChR subtypes. Meanwhile, we also conducted a competitive binding experiment between α-CTxs MII and LvIF, which showed that α-CTxs LvIF and MII bind with rα3β2 nAChR at the partial overlapping domain. These results indicate that the α-CTx LvIF has high potential as a new candidate tool for the studying of rα3β2 nAChR related neurophysiology and pharmacology.

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“…α-Conotoxins are among the smallest conopeptides from Conus venoms (12–20 amino acids (aa)). Classical α-conotoxins are characterised by a CC–X m –C–X n –C framework forming three possible disulfide connectivities: globular (I–III, II–IV), ribbon (I–IV, II–III) and bead (I–II, III–IV) ( Azam and Mcintosh, 2009 ; Lewis et al, 2012 ; Ho et al, 2020 ) with the globular conformation generally the native bioactive isomer. α-conotoxins are further divided into several structural subgroups ( m/n : 3/5, 5/5, 4/3, 4/4, 4/5, 4/6 and 4/7) based on the number of residues within the two loops ( m , n ) braced by the disulfide bonds.…”

Section: Introductionmentioning

confidence: 99%

Unique Pharmacological Properties of α-Conotoxin OmIA at α7 nAChRs

Abraham

Lewis

2021

Front. Pharmacol.

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OmIA, isolated from Conus omaria venom, is a potent antagonist at α7 nAChRs. We determined the co-crystal structure of OmIA with Lymnae stagnalis acetylcholine binding protein (Ls-AChBP) that identified His5, Val10 and Asn11 as key determinants for the high potency of OmIA at α7 nAChRs. Remarkably, despite a competitive binding mode observed in the co-crystal structure, OmIA and analogues displayed functional insurmountable antagonism at α7 and α3β4 nAChRs, except OmIA analogues having long side chain at position 10 ([V10Q]OmIA and [V10L]OmIA), which were partial insurmountable antagonist at α7 nAChRs in the presence of type II positive allosteric modulators (PAMs). A “two-state, two-step” model was used to explain these observations, with [V10Q]OmIA and [V10L]OmIA co-existing in a fast reversible/surmountable as well as a tight binding/insurmountable state. OmIA and analogues also showed biphasic-inhibition at α7 nAChRs in the presence of PNU120596, with a preference for the high-affinity binding site following prolonged exposure. The molecular basis of binding and complex pharmacological profile of OmIA at α7 nAChRs presented in here expands on the potential of α-conotoxins to probe the pharmacological properties of nAChRs and may help guide the development novel α7 modulators.

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Structure-Function of Neuronal Nicotinic Acetylcholine Receptor Inhibitors Derived From Natural Toxins

Cited by 49 publications

References 151 publications

Rigidity of loop 1 contributes to equipotency of globular and ribbon isomers of α-conotoxin AusIA

Rigidity of loop 1 contributes to equipotency of globular and ribbon isomers of α-conotoxin AusIA

Characterization of an α 4/7-Conotoxin LvIF from Conus lividus That Selectively Blocks α3β2 Nicotinic Acetylcholine Receptor

Unique Pharmacological Properties of α-Conotoxin OmIA at α7 nAChRs

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