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Homology modeling and dynamics of the extracellular domain of rat and human neuronal nicotinic acetylcholine receptor subtypes α4β2 and α7

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Abstract

In recent years, it has become clear that the neuronal nicotinic acetylcholine receptor (nAChR) is a valid target in the treatment of a variety of diseases, including Alzheimer’s disease, anxiety, and nicotine addiction. As with most membrane proteins, information on the three-dimensional (3D) structure of nAChR is limited to data from electron microscopy, at a resolution that makes the application of structure-based design approaches to develop specific ligands difficult. Based on a high-resolution crystal structure of AChBP, homology models of the extracellular domain of the neuronal rat and human nAChR subtypes α4β2 and α7 (the subtypes most abundant in brain) were built, and their stability assessed with molecular dynamics (MD). All models built showed conformational stability over time, confirming the quality of the starting 3D model. Lipophilicity and electrostatic potential studies performed on the rat and human α4β2 and α7 nicotinic models were compared to AChBP, revealing the importance of the hydrophobic aromatic pocket and the critical role of the α-subunit Trp—the homolog of AChBP-Trp 143—for ligand binding. The models presented provide a valuable framework for the structure-based design of specific α4β2 nAChR subtype ligands aimed at improving therapeutic and diagnostic applications.

Electrostatic surface potential of the binding site cavity of the neuronal nicotinic acetylcholine receptor (nAChR). Nicotinic models performed with the MOLCAD program: a rat α7, b rat α4β2, c human α7, d human α4β2. All residues labeled are part of the α7 (a,c) or α4 (b,d) subunit with the exception of Phe 117, which belongs to subunit β2 (d). Violet Very negative, blue negative, yellow neutral, red very positive

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References

  1. Karlin A (2002) Nat Rev Neurosci 3:102–114

    Article  CAS  Google Scholar 

  2. Sine SM, Engel AG (2006) Nature 440:448–455

    Article  CAS  Google Scholar 

  3. Badio B, Daly JW (1994) Mol Pharmacol 45:563–569

    CAS  Google Scholar 

  4. Arneric SP, Holladay M, Williams M (2007) Biochem Pharmacol 74:1092–1101

    Article  CAS  Google Scholar 

  5. Itièr V, Bertrand D (2001) FEBS Lett 504:118–125

    Article  Google Scholar 

  6. Hogg R, Bertrand D (2003) Drug News Perspect 16:261–266

    Article  CAS  Google Scholar 

  7. Miyazawa A, Fujiyoshi Y, Unwin N (2003) Nature 423:949–955

    Article  CAS  Google Scholar 

  8. Unwin NJ (2005) Mol Biol 346:967–989

    Article  CAS  Google Scholar 

  9. Brejc K, Van Dijk WJ, Klaassen RV, Schuurmans M, Van der Oost J, Smit AB, Sixma TK (2001) Nature 411:269–276

    Article  CAS  Google Scholar 

  10. Sixma TK, Smit AB (2003) Annu Rev Biophys Struct 32:311–334

    Article  CAS  Google Scholar 

  11. Celie PH, van Rossum-Fikkert SE, Van Dijk WJ, Brejc K, Smit AB, Sixma TK (2004) Neuron 41:907–914

    Article  CAS  Google Scholar 

  12. Celie PH, Kasheverov IE, Mordvintsev DY, Hogg RC, van Nierop P, van Elk R, van Rossum-Fikkert SE, Zhmak MN, Bertrand D, Tselin V, Sixma TK, Smit AB (2005) Nat Struct Mol Biol 12:582–588

    Article  CAS  Google Scholar 

  13. Taylor P, Talley TT, Radic Z, Hansen SB, Hibbs RE, Shi J (2007) Biochem Pharmacol 74:1164–1171

    Article  CAS  Google Scholar 

  14. Harel M, Kasher R, Nicolas A, Guss JM, Balass M, Fridkin M, Smit AB, Brejc K, Sixma TK, Katchalski-Katzir E, Sussman JL, Fuchs S (2001) Neuron 32:265–275

    Article  CAS  Google Scholar 

  15. Hansen SB, Radic Z, Talley TT, Molles BE, Deerinck T, Tsigelny I, Taylor P (2002) J Biol Chem 277:41299–41302

    Article  CAS  Google Scholar 

  16. Hansen SB, Radic Z, Talley TT, Taylor P (2003) Faseb J 17:A641–A641

    Google Scholar 

  17. Hansen SB, Talley TT, Radic Z, Taylor P (2004) J Biol Chem 279:24197–24202

    Article  CAS  Google Scholar 

  18. Law RJ, Henchman RH, McCammon JA (2005) Proc Natl Acad Sci USA 102:6813–6818

    Article  CAS  Google Scholar 

  19. Henchman RH, Wang H-L, Sine SM, Taylor P, McCammon JA (2005) Biophys J 88:2564–2576

    Article  CAS  Google Scholar 

  20. Zhang D, Gullingsrud J, McCammon JA (2006) J Am Chem Soc 128:3019–3026

    Article  CAS  Google Scholar 

  21. Taly A, Corringer P-J, Grutter T, de Carvalho LP, Karplus M, Changeux JP (2006) Proc Natl Acad Sci USA 103:16965–16970

    Article  CAS  Google Scholar 

  22. Szarecka A, Xu Y, Tang P (2007) Proteins 68:948–960

    Article  CAS  Google Scholar 

  23. Amiri S, Sansom MSP, Biggin PC (2007) Protein Eng Des Sel 20:353–359

    Article  CAS  Google Scholar 

  24. Stoye J (1998) Gene 211:45–56

    Article  Google Scholar 

  25. Guex N, Peitsch MC (1997) Electrophoresis 18:2714–2723

    Article  CAS  Google Scholar 

  26. Peitsch MC (1996) Biochem Soc Trans 24:274–279

    CAS  Google Scholar 

  27. Peitsch MC (1995) Biotechnology 13:658–660

    Article  CAS  Google Scholar 

  28. http://igc.ethz.ch/gromos

  29. Le Novère N, Grutter T, Changeux JP (2002) Proc Natl Acad Sci USA 99:3210–3215

    Article  Google Scholar 

  30. Laskowski RA, MacArthur MW, Moss DS, Thornton JM (1993) J Appl Crystallogr 26:283–291

    Article  CAS  Google Scholar 

  31. Zhong W, Gallivan JP, Zhang Y, Li L, Lester HA, Dougherty DA (1998) Proc Natl Acad Sci USA 95:12088–12093

    Article  CAS  Google Scholar 

  32. Schmitt JD, Sharples CGV, Caldwell WS (1999) J Med Chem 42:3066–3074

    Article  CAS  Google Scholar 

  33. http://amber.scripps.edu/doc6/amber6.pdf

  34. Cornell WD, Cieplak P, Bayly CI, Gould IR, Merz KM, Ferguson DM, Spellmeyer DC, Fox T, Caldwell JW, Kollman PA (1995) J Am Chem Soc 117:5179–5197

    Article  CAS  Google Scholar 

  35. Berendsen HJC, Postma JPM, van Gunsteren WF, DiNola A, Haak JRJ (1984) Chem Phys 81:3684–3690

    Article  CAS  Google Scholar 

  36. Brickmann J, Goetze T, Heiden W, Moeckel G, Reiling S, Vollhardt H, Zachmann C-D (1995) Data visualization in molecular science: tools for insight and innovation. Addison-Wesley, Reading, MA

    Google Scholar 

  37. Lukas RJ (1998) The nicotinic acetylcholine receptor: current views and future trends. Springer, Berlin

    Google Scholar 

  38. Jensen AA, Zlotos DP, Liljefors TJ (2007) J Med Chem 50:4616–4629

    Article  CAS  Google Scholar 

  39. Bisson WH, Scapozza L, Westera G, Mu L, Schubiger PA (2005) J Med Chem 48:5123–5130

    Article  CAS  Google Scholar 

  40. Huang X, Miller W (1991) Adv Appl Math 12:373–381

    Article  Google Scholar 

Download references

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Author notes

  1. William H. Bisson

    Present address: The Scripps Research Institute, 10550 North Torrey Pines Rd, La Jolla, CA, 92037, USA

Authors and Affiliations

  1. Center for Radiopharmaceutical Sciences, Paul Scherrer Institute, Villigen and University Hospital of Zürich, Swiss Federal Institute of Technology Zurich, Ramistrasse 100, 8091, Zurich, Switzerland

    William H. Bisson, Gerrit Westera & P. Augustus Schubiger

  2. Pharmaceutical Biochemistry Group, School of Pharmaceutical Sciences, University of Geneva, 24 rue du General-Dufour, 1211, Geneva, Switzerland

    Leonardo Scapozza

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  1. William H. Bisson
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  2. Gerrit Westera
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  3. P. Augustus Schubiger
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  4. Leonardo Scapozza
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Correspondence to William H. Bisson.

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Bisson, W.H., Westera, G., Schubiger, P.A. et al. Homology modeling and dynamics of the extracellular domain of rat and human neuronal nicotinic acetylcholine receptor subtypes α4β2 and α7. J Mol Model 14, 891–899 (2008). https://doi.org/10.1007/s00894-008-0340-x

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  • DOI: https://doi.org/10.1007/s00894-008-0340-x

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