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The 1.1 Å Resolution Crystal Structure of [Tyr15]EpI, a Novel α-Conotoxin from Conus episcopatus, Solved by Direct Methods

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    The 1.1 Å Resolution Crystal Structure of [Tyr15]EpI, a Novel α-Conotoxin from Conus episcopatus, Solved by Direct Methods†
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    Centre for Drug Design and Development, University of Queensland, Brisbane, QLD 4072 Australia, Department of Computer Science, State University of New York at Buffalo, Buffalo, New York 14260, and Hauptman-Woodward Medical Research Institute, 73 High Street, Buffalo, New York 14203
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    Biochemistry

    Cite this: Biochemistry 1998, 37, 33, 11425–11433
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    https://doi.org/10.1021/bi9806549
    Published July 25, 1998
    Copyright © 1998 American Chemical Society
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    Abstract

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    Conotoxins are valuable probes of receptors and ion channels because of their small size and highly selective activity. α-Conotoxin EpI, a 16-residue peptide from the mollusk-hunting Conus episcopatus, has the amino acid sequence GCCSDPRCNMNNPDY(SO3H)C-NH2 and appears to be an extremely potent and selective inhibitor of the α3β2 and α3β4 neuronal subtypes of the nicotinic acetylcholine receptor (nAChR). The desulfated form of EpI ([Tyr15]EpI) has a potency and selectivity for the nAChR receptor similar to those of EpI. Here we describe the crystal structure of [Tyr15]EpI solved at a resolution of 1.1 Å using SnB. The asymmetric unit has a total of 284 non-hydrogen atoms, making this one of the largest structures solved de novo by direct methods. The [Tyr15]EpI structure brings to six the number of α-conotoxin structures that have been determined to date. Four of these, [Tyr15]EpI, PnIA, PnIB, and MII, have an α4/7 cysteine framework and are selective for the neuronal subtype of the nAChR. The structure of [Tyr15]EpI has the same backbone fold as the other α4/7-conotoxin structures, supporting the notion that this conotoxin cysteine framework and spacing give rise to a conserved fold. The surface charge distribution of [Tyr15]EpI is similar to that of PnIA and PnIB but is likely to be different from that of MII, suggesting that [Tyr15]EpI and MII may have different binding modes for the same receptor subtype.

    Copyright © 1998 American Chemical Society

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    †

     This work was supported by the Australian Industry Research and Development Board, AMRAD Operations Pty. Ltd., and the Australian Research Council. J.L.M. is supported by a Queen Elizabeth II Fellowship.

    ‡

     University of Queensland.

    §

     State University of New York at Buffalo.

    ‖

     Hauptman-Woodward Medical Research Institute.

    *

     To whom correspondence should be addressed. Phone:  +61 7 3365 4942. Fax:  +61 7 3365 1990. E-mail:  [email protected].

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    30. Jee-Hyun Cho, K.Hun Mok, Baldomero M. Olivera, J.Michael McIntosh, Kyu-Hwan Park, Kyou-Hoon Han. Nuclear Magnetic Resonance Solution Conformation of α-Conotoxin AuIB, an α3β4 Subtype-selective Neuronal Nicotinic Acetylcholine Receptor Antagonist. Journal of Biological Chemistry 2000, 275 (12) , 8680-8685. https://doi.org/10.1074/jbc.275.12.8680
    31. J. M. Mcintosh. Toxin Antagonists of the Neuronal Nicotinic Acetylcholine Receptor. 2000, 455-476. https://doi.org/10.1007/978-3-642-57079-7_17
    32. Aldo Franco, Frank Marí. Three-dimensional structure of α-conotoxin EI determined by1H NMR spectroscopy. Letters in Peptide Science 1999, 6 (4) , 199-207. https://doi.org/10.1007/BF02443507
    33. J. Michael McIntosh, Ameurfina D. Santos, Baldomero M. Olivera. Conus Peptides Targeted to Specific Nicotinic Acetylcholine Receptor Subtypes. Annual Review of Biochemistry 1999, 68 (1) , 59-88. https://doi.org/10.1146/annurev.biochem.68.1.59
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    35. Innokenty V Maslennikov, Zakhar O Shenkarev, Maxim N Zhmak, Vadim T Ivanov, Christoph Methfessel, Victor I Tsetlin, Alexander S Arseniev. NMR spatial structure of α‐conotoxin ImI reveals a common scaffold in snail and snake toxins recognizing neuronal nicotinic acetylcholine receptors 1. FEBS Letters 1999, 444 (2-3) , 275-280. https://doi.org/10.1016/S0014-5793(99)00069-1
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    Biochemistry

    Cite this: Biochemistry 1998, 37, 33, 11425–11433
    Click to copy citationCitation copied!
    https://doi.org/10.1021/bi9806549
    Published July 25, 1998
    Copyright © 1998 American Chemical Society
    Request reuse permissions

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