Nicotinic acetylcholine receptors: α-conotoxins as templates for rational drug design

2003 ◽  
Vol 31 (3) ◽  
pp. 634-636 ◽  
Author(s):  
Robert W. Janes
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Structural Features ◽  
Docking Studies ◽  
Rational Drug Design ◽  
Synaptic Membranes ◽  
Nicotinic Acetylcholine ◽  
Computational Docking ◽  
Acetylcholine Binding Protein ◽  
Topological Features

Nicotinic acetylcholine receptors (nAChRs) mediate the passage of potassium and sodium ions across synaptic membranes. Two classes of receptors exist: the neuromuscular nAChRs, which mediate signals between nerve and muscle cells, and the neuronal nAChRs, which are found throughout the nervous system. For treatment of diseases involving nAChRs, drugs must be designed with a high level of selectivity towards only one of these classes or subclasses (in the case of neuronal receptors). α-Conotoxins, small polypeptides isolated from the venoms of marine snails, represent molecules with just this type of selectivity, with specificity even towards certain subclasses of nAChRs. The availability of high-resolution crystal structures of α-conotoxins provides the opportunity to examine the structural features that orchestrate their preferential blocking action. In the present study of a neuromuscular- and a neuronal-specific α-conotoxin, SI and EpI respectively, important and significant differences can be seen in the shapes of the molecules, which must reflect topological features of the different types of target receptor subunits. These then provide a template for computational docking studies with the homologous acetylcholine-binding protein, whose structure is known, so drug analogues of the naturally occurring toxins can be developed with the desired specificities.

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

2020 ◽  
Vol 14 ◽  
Author(s):  
Thao N. T. Ho ◽  
Nikita Abraham ◽  
Richard J. Lewis
Keyword(s):  
Drug Design ◽  
Ligand Binding ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Molecular Mechanisms ◽  
Rational Drug Design ◽  
Comprehensive Overview ◽  
Nicotinic Acetylcholine ◽  
Structure Based Drug Design ◽  
Selective Ligand

Neuronal nicotinic acetylcholine receptors (nAChRs) are prototypical cation-selective, ligand-gated ion channels that mediate fast neurotransmission in the central and peripheral nervous systems. nAChRs are involved in a range of physiological and pathological functions and hence are important therapeutic targets. Their subunit homology and diverse pentameric assembly contribute to their challenging pharmacology and limit their drug development potential. Toxins produced by an extensive range of algae, plants and animals target nAChRs, with many proving pivotal in elucidating receptor pharmacology and biochemistry, as well as providing templates for structure-based drug design. The crystal structures of these toxins with diverse chemical profiles in complex with acetylcholine binding protein (AChBP), a soluble homolog of the extracellular ligand-binding domain of the nAChRs and more recently the extracellular domain of human α9 nAChRs, have been reported. These studies have shed light on the diverse molecular mechanisms of ligand-binding at neuronal nAChR subtypes and uncovered critical insights useful for rational drug design. This review provides a comprehensive overview and perspectives obtained from structure and function studies of diverse plant and animal toxins and their associated inhibitory mechanisms at neuronal nAChRs.

scholarly journals Potency- and Selectivity-Enhancing Mutations of Conotoxins for Nicotinic Acetylcholine Receptors Can Be Predicted Using Accurate Free-Energy Calculations

Marine Drugs ◽  
2021 ◽  
Vol 19 (7) ◽  
pp. 367
Author(s):  
Dana Katz ◽  
Michael A. DiMattia ◽  
Dan Sindhikara ◽  
Hubert Li ◽  
Nikita Abraham ◽  
...  
Keyword(s):  
Free Energy ◽  
Crystal Structures ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Drug Targets ◽  
Point Mutations ◽  
Free Energy Calculations ◽  
Nicotinic Acetylcholine ◽  
Acetylcholine Binding Protein ◽  
Energy Perturbation

Nicotinic acetylcholine receptor (nAChR) subtypes are key drug targets, but it is challenging to pharmacologically differentiate between them because of their highly similar sequence identities. Furthermore, α-conotoxins (α-CTXs) are naturally selective and competitive antagonists for nAChRs and hold great potential for treating nAChR disorders. Identifying selectivity-enhancing mutations is the chief aim of most α-CTX mutagenesis studies, although doing so with traditional docking methods is difficult due to the lack of α-CTX/nAChR crystal structures. Here, we use homology modeling to predict the structures of α-CTXs bound to two nearly identical nAChR subtypes, α3β2 and α3β4, and use free-energy perturbation (FEP) to re-predict the relative potency and selectivity of α-CTX mutants at these subtypes. First, we use three available crystal structures of the nAChR homologue, acetylcholine-binding protein (AChBP), and re-predict the relative affinities of twenty point mutations made to the α-CTXs LvIA, LsIA, and GIC, with an overall root mean square error (RMSE) of 1.08 ± 0.15 kcal/mol and an R2 of 0.62, equivalent to experimental uncertainty. We then use AChBP as a template for α3β2 and α3β4 nAChR homology models bound to the α-CTX LvIA and re-predict the potencies of eleven point mutations at both subtypes, with an overall RMSE of 0.85 ± 0.08 kcal/mol and an R2 of 0.49. This is significantly better than the widely used molecular mechanics—generalized born/surface area (MM-GB/SA) method, which gives an RMSE of 1.96 ± 0.24 kcal/mol and an R2 of 0.06 on the same test set. Next, we demonstrate that FEP accurately classifies α3β2 nAChR selective LvIA mutants while MM-GB/SA does not. Finally, we use FEP to perform an exhaustive amino acid mutational scan of LvIA and predict fifty-two mutations of LvIA to have greater than 100X selectivity for the α3β2 nAChR. Our results demonstrate the FEP is well-suited to accurately predict potency- and selectivity-enhancing mutations of α-CTXs for nAChRs and to identify alternative strategies for developing selective α-CTXs.

scholarly journals Pursuing High-Resolution Structures of Nicotinic Acetylcholine Receptors: Lessons Learned from Five Decades

Molecules ◽  
2021 ◽  
Vol 26 (19) ◽  
pp. 5753
Author(s):  
Manuel Delgado-Vélez ◽  
Orestes Quesada ◽  
Juan C. Villalobos-Santos ◽  
Rafael Maldonado-Hernández ◽  
Guillermo Asmar-Rovira ◽  
...  
Keyword(s):  
High Resolution ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Structural Features ◽  
Lessons Learned ◽  
Nicotinic Acetylcholine ◽  
Disease States ◽  
Pharmacological Targets ◽  
Therapeutic Value ◽  
Effective Drugs

Since their discovery, nicotinic acetylcholine receptors (nAChRs) have been extensively studied to understand their function, as well as the consequence of alterations leading to disease states. Importantly, these receptors represent pharmacological targets to treat a number of neurological and neurodegenerative disorders. Nevertheless, their therapeutic value has been limited by the absence of high-resolution structures that allow for the design of more specific and effective drugs. This article offers a comprehensive review of five decades of research pursuing high-resolution structures of nAChRs. We provide a historical perspective, from initial structural studies to the most recent X-ray and cryogenic electron microscopy (Cryo-EM) nAChR structures. We also discuss the most relevant structural features that emerged from these studies, as well as perspectives in the field.

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

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Thao N. T. Ho ◽  
Nikita Abraham ◽  
Richard J. Lewis
Keyword(s):  
Crystal Structures ◽  
Nicotinic Acetylcholine Receptors ◽  
Molecular Basis ◽  
Disulfide Bonds ◽  
Acetylcholine Receptors ◽  
Binding Protein ◽  
Wild Type ◽  
Critical Determinant ◽  
Nicotinic Acetylcholine ◽  
Acetylcholine Binding Protein

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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