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Crystal structure of nicotinic acetylcholine receptor homolog AChBP in complex with an α-conotoxin PnIA variant

Nature Structural & Molecular Biology volume 12, pages 582–588 (2005)Cite this article

Abstract

Conotoxins (Ctx) form a large family of peptide toxins from cone snail venoms that act on a broad spectrum of ion channels and receptors. The subgroup α-Ctx specifically and selectively binds to subtypes of nicotinic acetylcholine receptors (nAChRs), which are targets for treatment of several neurological disorders. Here we present the structure at a resolution of 2.4 Å of α-Ctx PnIA (A10L D14K), a potent blocker of the α7-nAChR, bound with high affinity to acetylcholine binding protein (AChBP), the prototype for the ligand-binding domains of the nAChR superfamily. α-Ctx is buried deep within the ligand-binding site and interacts with residues on both faces of adjacent subunits. The toxin itself does not change conformation, but displaces the C loop of AChBP and induces a rigid-body subunit movement. Knowledge of these contacts could facilitate the rational design of drug leads using the Ctx framework and may lead to compounds with increased receptor subtype selectivity.

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Figure 1: Effect of α-Ctx on ACh-induced currents on α7-nAChR.
Figure 2: Crystal structure of α-conotoxin binding to Ac-AChBP.
Figure 3: Details of α-conotoxin interaction with Ac-AChBP.
Figure 4: Conformational changes in AChBP upon toxin binding.
Figure 5: Models of α-conotoxin binding to other ligand-binding domains.

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Acknowledgements

We thank Y. Utkin for providing snake venom toxins and fruitful discussions, beamline staff at European Synchrotron Radiation Facility Grenoble for assistance with data collection and K. Brejc and C. Ulens for critically reading the manuscript. The work was supported by a NWO-RFBR grant (A.B.S. and V.I.T.) and in part by MCB RAN grant (V.I.T.), by STW-BBC6035 (T.K.S. and A.B.S.), by NWO-CW 98016 (T.K.S.) and EU-SPINE (T.K.S).

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Author notes

  1. Patrick H N Celie and Igor E Kasheverov: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066 CX, The Netherlands

    Patrick H N Celie, Sarah E van Rossum-Fikkert & Titia K Sixma

  2. Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Science, 16/10 Miklukho-Maklaya str., Moscow, 117977, Russia

    Igor E Kasheverov, Dmitry Y Mordvintsev, Maxim N Zhmak & Victor Tsetlin

  3. Department of Neuroscience, Centre Medical Universitaire, Medical Faculty, 1 rue Michel Servet, Geneva, CH-1211 4, Switzerland

    Ronald C Hogg & Daniel Bertrand

  4. Department of Molecular and Cellular Neurobiology, Center for Neurogenomics and Cognitive Research, Faculty of Earth and Life Sciences, Vrije Universiteit, De Boelelaan 1085, Amsterdam, 1081 HV, The Netherlands

    Pim van Nierop, René van Elk & August B Smit

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Correspondence to August B Smit.

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Supplementary information

Supplementary Table 1

Thermodynamic parameters. (PDF 60 kb)

Supplementary Table 2

Contacts of α-conotoxin with AChBP and α7-nAChR. (PDF 92 kb)

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Celie, P., Kasheverov, I., Mordvintsev, D. et al. Crystal structure of nicotinic acetylcholine receptor homolog AChBP in complex with an α-conotoxin PnIA variant. Nat Struct Mol Biol 12, 582–588 (2005). https://doi.org/10.1038/nsmb951

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