Structures of Aplysia AChBP Complexes with Nicotinic Agonists and Antagonists Reveal Distinctive Binding Interfaces and Conformations

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2005 Sep 30

PMID 16193063

Citations 299

Authors

Scott B Hansen

Gerlind Sulzenbacher

Tom Huxford

Pascale Marchot

Palmer Taylor

Yves Bourne

Affiliations

Soon will be listed here.

Abstract

Upon ligand binding at the subunit interfaces, the extracellular domain of the nicotinic acetylcholine receptor undergoes conformational changes, and agonist binding allosterically triggers opening of the ion channel. The soluble acetylcholine-binding protein (AChBP) from snail has been shown to be a structural and functional surrogate of the ligand-binding domain (LBD) of the receptor. Yet, individual AChBP species display disparate affinities for nicotinic ligands. The crystal structure of AChBP from Aplysia californica in the apo form reveals a more open loop C and distinctive positions for other surface loops, compared with previous structures. Analysis of Aplysia AChBP complexes with nicotinic ligands shows that loop C, which does not significantly change conformation upon binding of the antagonist, methyllycaconitine, further opens to accommodate the peptidic antagonist, alpha-conotoxin ImI, but wraps around the agonists lobeline and epibatidine. The structures also reveal extended and nonoverlapping interaction surfaces for the two antagonists, outside the binding loci for agonists. This comprehensive set of structures reflects a dynamic template for delineating further conformational changes of the LBD of the nicotinic receptor.

Citing Articles

A Pharmacophore for Drugs Targeting the α4α4 Binding Site of the (α4)(β2) Nicotinic Acetylcholine Receptor.

Kusay A, Luo Y, OMara M, Balle T J Neurochem. 2025; 169(2):e70000.

PMID: 39967313 PMC: 11836552. DOI: 10.1111/jnc.70000.

Conformational dynamics of a nicotinic receptor neurotransmitter site.

Singh M, Indurthi D, Mittal L, Auerbach A, Asthana S Elife. 2024; 13.

PMID: 39693137 PMC: 11655062. DOI: 10.7554/eLife.92418.

Molecular determinants of the selectivity and potency of α-conotoxin Vc1.1 for human nicotinic acetylcholine receptors.

Tae H, Hung A, Clark R, Adams D J Biol Chem. 2024; 301(1):108017.

PMID: 39608712 PMC: 11732461. DOI: 10.1016/j.jbc.2024.108017.

Protein Painting Mass Spectrometry in the Discovery of Interaction Sites within the Acetylcholine Binding Protein.

Graur A, Haymond A, Lee K, Viscarra F, Russo P, Luchini A ACS Chem Neurosci. 2024; 15(11):2322-2333.

PMID: 38804618 PMC: 11157483. DOI: 10.1021/acschemneuro.4c00149.

The Cyclic Imine Core Common to the Marine Macrocyclic Toxins Is Sufficient to Dictate Nicotinic Acetylcholine Receptor Antagonism.

Bourne Y, Sulzenbacher G, Chabaud L, Araoz R, Radic Z, Conrod S Mar Drugs. 2024; 22(4).

PMID: 38667766 PMC: 11050823. DOI: 10.3390/md22040149.

References

Maslennikov I, Shenkarev Z, Zhmak M, Ivanov V, Methfessel C, Tsetlin V . NMR spatial structure of alpha-conotoxin ImI reveals a common scaffold in snail and snake toxins recognizing neuronal nicotinic acetylcholine receptors. FEBS Lett. 1999; 444(2-3):275-80. DOI: 10.1016/s0014-5793(99)00069-1. View

Rogers J, Luginbuhl P, Shen G, McCabe R, Stevens R, Wemmer D . NMR solution structure of alpha-conotoxin ImI and comparison to other conotoxins specific for neuronal nicotinic acetylcholine receptors. Biochemistry. 1999; 38(13):3874-82. DOI: 10.1021/bi9826254. View

Perrakis A, Morris R, Lamzin V . Automated protein model building combined with iterative structure refinement. Nat Struct Biol. 1999; 6(5):458-63. DOI: 10.1038/8263. View

Flammia D, Dukat M, Damaj M, Martin B, Glennon R . Lobeline: structure-affinity investigation of nicotinic acetylcholinergic receptor binding. J Med Chem. 1999; 42(18):3726-31. DOI: 10.1021/jm990286m. View

Tsetlin V . Snake venom alpha-neurotoxins and other 'three-finger' proteins. Eur J Biochem. 1999; 264(2):281-6. DOI: 10.1046/j.1432-1327.1999.00623.x. View

Smit A, Syed N, Schaap D, van Minnen J, Klumperman J, Kits K . A glia-derived acetylcholine-binding protein that modulates synaptic transmission. Nature. 2001; 411(6835):261-8. DOI: 10.1038/35077000. View

Brejc K, VAN DIJK W, Klaassen R, Schuurmans M, van der Oost J, Smit A . Crystal structure of an ACh-binding protein reveals the ligand-binding domain of nicotinic receptors. Nature. 2001; 411(6835):269-76. DOI: 10.1038/35077011. View

Grutter T, Changeux J . Nicotinic receptors in wonderland. Trends Biochem Sci. 2001; 26(8):459-63. DOI: 10.1016/s0968-0004(01)01921-1. View

Karlin A . Emerging structure of the nicotinic acetylcholine receptors. Nat Rev Neurosci. 2002; 3(2):102-14. DOI: 10.1038/nrn731. View

10.

Hansen S, Radic Z, Talley T, Molles B, Deerinck T, Tsigelny I . Tryptophan fluorescence reveals conformational changes in the acetylcholine binding protein. J Biol Chem. 2002; 277(44):41299-302. PMC: 3191908. DOI: 10.1074/jbc.C200462200. View

11.

Reeves P, Callewaert N, Contreras R, Khorana H . Structure and function in rhodopsin: high-level expression of rhodopsin with restricted and homogeneous N-glycosylation by a tetracycline-inducible N-acetylglucosaminyltransferase I-negative HEK293S stable mammalian cell line. Proc Natl Acad Sci U S A. 2002; 99(21):13419-24. PMC: 129688. DOI: 10.1073/pnas.212519299. View

12.

Ellison M, McIntosh J, Olivera B . Alpha-conotoxins ImI and ImII. Similar alpha 7 nicotinic receptor antagonists act at different sites. J Biol Chem. 2002; 278(2):757-64. DOI: 10.1074/jbc.M204565200. View

13.

Sulzenbacher G, Gruez A, Roig-Zamboni V, Spinelli S, Valencia C, Pagot F . A medium-throughput crystallization approach. Acta Crystallogr D Biol Crystallogr. 2002; 58(Pt 12):2109-15. DOI: 10.1107/s0907444902013938. View

14.

Sakmann B . Elementary steps in synaptic transmission revealed by currents through single ion channels. Science. 1992; 256(5056):503-12. DOI: 10.1126/science.1373907. View

15.

Richman D, Agius M . Treatment of autoimmune myasthenia gravis. Neurology. 2003; 61(12):1652-61. DOI: 10.1212/01.wnl.0000098887.24618.a0. View

16.

Celie P, van Rossum-Fikkert S, van Dijk W, Brejc K, Smit A, Sixma T . Nicotine and carbamylcholine binding to nicotinic acetylcholine receptors as studied in AChBP crystal structures. Neuron. 2004; 41(6):907-14. DOI: 10.1016/s0896-6273(04)00115-1. View

17.

Hansen S, Talley T, Radic Z, Taylor P . Structural and ligand recognition characteristics of an acetylcholine-binding protein from Aplysia californica. J Biol Chem. 2004; 279(23):24197-202. PMC: 4762456. DOI: 10.1074/jbc.M402452200. View

18.

Lester H, Dibas M, Dahan D, Leite J, Dougherty D . Cys-loop receptors: new twists and turns. Trends Neurosci. 2004; 27(6):329-36. DOI: 10.1016/j.tins.2004.04.002. View

19.

Nicke A, Wonnacott S, Lewis R . Alpha-conotoxins as tools for the elucidation of structure and function of neuronal nicotinic acetylcholine receptor subtypes. Eur J Biochem. 2004; 271(12):2305-19. DOI: 10.1111/j.1432-1033.2004.04145.x. View

20.

Bergmeier S, Ismail K, Arason K, McKay S, Bryant D, McKay D . Structure activity studies of ring E analogues of methyllycaconitine. Part 2: Synthesis of antagonists to the alpha3beta4* nicotinic acetylcholine receptors through modifications to the ester. Bioorg Med Chem Lett. 2004; 14(14):3739-42. DOI: 10.1016/j.bmcl.2004.05.001. View