Three-dimensional structure of α-conotoxin EI determined by1H NMR spectroscopy

Franco, Aldo; Marí, Frank

doi:10.1007/bf02443507

Cited by 6 publications

(5 citation statements)

References 39 publications

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“…There are no solution structures reported for these molecules, but ImI has the same first loop as EpI, and four independent solution structures of ImI have been reported. An N-terminal 3 10 helical motif is reported in just one of the four ImI NMR structures (16), and no other NMR structures of ␣-conotoxins report this element of secondary structure (9,(11)(12)(13)(14)(15)17). In the structure described here a 3 10 helix is detected in 6 of 20 AuIB structures.…”

Section: Fig 7 Effect Of Native and Ribbon Isomers Of Auib On Nicotmentioning

confidence: 99%

A New Level of Conotoxin Diversity, a Non-native Disulfide Bond Connectivity in α-Conotoxin AuIB Reduces Structural Definition but Increases Biological Activity

Dutton

Bansal

Hogg

et al. 2002

Journal of Biological Chemistry

115

129

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␣-Conotoxin AuIB and a disulfide bond variant of AuIB have been synthesized to determine the role of disulfide bond connectivity on structure and activity. Both of these peptides contain the 15 amino acid sequence GCCSYPPCFATNPDC, with the globular (native) isomer having the disulfide connectivity Cys(2-8 and 3-15) and the ribbon isomer having the disulfide connectivity Cys(2-15 and 3-8). The solution structures of the peptides were determined by NMR spectroscopy, and their ability to block the nicotinic acetylcholine receptors on dissociated neurons of the rat parasympathetic ganglia was examined. The ribbon disulfide isomer, although having a less well defined structure, is surprisingly found to have approximately 10 times greater potency than the native peptide. To our knowledge this is the first demonstration of a non-native disulfide bond isomer of a conotoxin exhibiting greater biological activity than the native isomer.

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Section: Fig 7 Effect Of Native and Ribbon Isomers Of Auib On Nicotmentioning

confidence: 99%

A New Level of Conotoxin Diversity, a Non-native Disulfide Bond Connectivity in α-Conotoxin AuIB Reduces Structural Definition but Increases Biological Activity

Dutton

Bansal

Hogg

et al. 2002

Journal of Biological Chemistry

115

129

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“…1MTQ). The similar backbone topology of these α-conotoxins suggests that differences in the nAChR rank order of potency among these toxins should originate from differences in the surface charge and size of the side chains [17,39,40]. The Nterminal disulphide loop of all of these α-conotoxins contains a reasonably hydrophobic SνPψ motif (shown in grey in Figure 3), where ν is a variable residue and ψ is a hydrophobic residue, except for α-conotoxin EpI.…”

Section: Structural Comparison Of α-Conotoxin Gic With Other α3β2-blomentioning

confidence: 99%

Solution conformation of alpha-conotoxin GIC, a novel potent antagonist of alpha3beta2 nicotinic acetylcholine receptors

Chi

Kim

Olivera

et al. 2004

Biochemical Journal

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Alpha-conotoxin GIC is a 16-residue peptide isolated from the venom of the cone snail Conus geographus. Alpha-conotoxin GIC potently blocks the alpha3beta2 subtype of human nicotinic acetylcholine receptor, showing a high selectivity for neuronal versus muscle subtype [McIntosh, Dowell, Watkins, Garrett, Yoshikami, and Olivera (2002) J. Biol. Chem. 277, 33610-33615]. We have now determined the three-dimensional solution structure of alpha-conotoxin GIC by NMR spectroscopy. The structure of alpha-conotoxin GIC is well defined with backbone and heavy atom root mean square deviations (residues 2-16) of 0.53 A and 0.96 A respectively. Structure and surface comparison of alpha-conotoxin GIC with the other alpha4/7 subfamily conotoxins reveals unique structural aspects of alpha-conotoxin GIC. In particular, the structural comparison between alpha-conotoxins GIC and MII indicates molecular features that may confer their similar receptor specificity profile, as well as those that provide the unique binding characteristics of alpha-conotoxin GIC.

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“…It is remarkable that the backbone root mean square deviations among the six ␣4/7 subfamily members are less than 1.0 Å. The fact that the backbone topology of these ␣4/7 conotoxins is virtually the same suggests that differences in the receptor subtype specificities among these toxins are likely to be mediated by differences in the surface charge and size of the side chains (34,47,50).…”

Section: Nmr Spectroscopy-completementioning

confidence: 99%

Solution Conformation of α-Conotoxin EI, a Neuromuscular Toxin Specific for the α1/δ Subunit Interface of Torpedo Nicotinic Acetylcholine Receptor

Park¹,

Suk²,

Jacobsen³

et al. 2001

Journal of Biological Chemistry

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A high resolution structure of ␣-conotoxin EI has been determined by 1 H NMR spectroscopy and molecular modeling. ␣-Conotoxin EI has the same disulfide framework as ␣4/7 conotoxins targeting neuronal nicotinic acetylcholine receptors but antagonizes the neuromuscular receptor as do the ␣3/5 and ␣A conotoxins. The unique binding preference of ␣-conotoxin EI to the ␣ 1 /␦ subunit interface of Torpedo neuromuscular receptor makes it a valuable structural template for superposition of various ␣-conotoxins possessing distinct receptor subtype specificities. Structural comparison of ␣-conotoxin EI with the ␥-subunit favoring ␣-conotoxin GI suggests that the Torpedo ␦-subunit preference of the former originates from its second loop. Superposition of three-dimensional structures of seven ␣-conotoxins reveals that the estimated size of the toxin-binding pocket in nicotinic acetylcholine receptor is ϳ20 Å (height) ؋ 20 Å (width) ؋ 15 Å (thickness).The nicotinic acetylcholine receptors (nAChRs) 1 are a well studied family of ligand-gated ion channels comprising a diverse set of molecular subtypes (1). The best characterized is the receptor at the neuromuscular junction, with four different subunits in a pentameric array, i.e. (␣ 1 ) 2 ␤ 1␥ ␦. Less well understood and more diverse are the neuronal nAChRs that assemble in exogenous expression systems with a general composition of (␣ m ) 2 (␤ n ) 3 , where m ϭ 2-6 and n ϭ 2-4, or (␣ 7 ) 5 (2, 3). A large variety of ligands bind to such diverse nAChRs via unknown mechanisms. A better understanding of the ligandbinding mechanism would be possible if a suitable three-dimensional structure of nAChR were available. Although cryoelectron microscopic images of nAChR show the spatial arrangement of five subunits of the receptor and some aspects of the ligand-binding pockets (4, 5), they are as yet insufficient for describing ligand-receptor interactions in atomic detail. In this regard, the recently determined crystal structure of acetylcholine-binding protein is expected to provide useful insight into ligand-nAChR interactions (6).Small peptide toxins of Conus origin known as the ␣-and ␣A-conotoxins are highly useful tools for exploring ligandnAChR interactions (7,8). A well defined subgroup of ␣-conotoxins, referred to as the ␣3/5 2 subfamily conotoxins (Table I), are antagonists of neuromuscular receptors and show, except for ␣-conotoxin SI (9, 10), binding preference to the ␣ 1 /␥ subunit interface of Torpedo nAChR. On the other hand, more recently found ␣A-conotoxins differ from the ␣3/5 subfamily conotoxins in the amino acid sequences (11, 12) as well as in their threedimensional structures (13). The ␣A-conotoxins, nevertheless, target neuromuscular receptors. A third subfamily of ␣-conotoxins known as the ␣4/7 subfamily has also been found; members of this subfamily target subtypes of neuronal and muscle nAChRs (14 -17). The ␣4/7 subfamily contains two disulfide bonds like the ␣3/5 subfamily but has a different spacing between the disulfide bonds.Even though a high resolutio...

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Three-dimensional structure of α-conotoxin EI determined by1H NMR spectroscopy

Cited by 6 publications

References 39 publications

A New Level of Conotoxin Diversity, a Non-native Disulfide Bond Connectivity in α-Conotoxin AuIB Reduces Structural Definition but Increases Biological Activity

A New Level of Conotoxin Diversity, a Non-native Disulfide Bond Connectivity in α-Conotoxin AuIB Reduces Structural Definition but Increases Biological Activity

Solution conformation of alpha-conotoxin GIC, a novel potent antagonist of alpha3beta2 nicotinic acetylcholine receptors

Solution Conformation of α-Conotoxin EI, a Neuromuscular Toxin Specific for the α1/δ Subunit Interface of Torpedo Nicotinic Acetylcholine Receptor

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