Skip to main content

Advertisement

SpringerLink
Log in

In silico point mutation and evolutionary trace analysis applied to nicotinic acetylcholine receptors in deciphering ligand-binding surfaces

  • Original Paper
  • Published:
Journal of Molecular Modeling Aims and scope Submit manuscript

Abstract

The nicotinic acetylcholine receptors (nAChRs) are members of the Cys-loop superfamily and contain ligand gated ion channels (LGIC). These receptors are located mostly in the central nervous system (CNS) and peripheral nervous system (PNS). nAChRs reside at pre-synaptic regions to mediate acetylcholine neurotransmission and in the post synaptic membrane to propagate nerve impulses through neurons via acetylcholine. Malfunction of this neurotransmitter receptor is believed to cause various neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease and schizophrenia, and nAChRs are thus important drug targets. In the present work, starting from an earlier model of pentameric α7nAChR, a considerable effort has been taken to investigate interaction with ligands by performing docking studies with a diverse array of agonists and antagonists. Analysis of these docking complexes reveals identification of possible ligand-interacting residues. Some of these residues, e.g. Ser34, Gln55, Ser146, and Tyr166, which are evolutionarily conserved, were specifically subjected to virtual mutations based on their amino acid properties and found to be highly sensitive in the presence of antagonists by docking. Further, the study was extended using evolutionary trace analysis, revealing conserved and class-specific residues close to the putative ligand-binding site, further supporting the results of docking experiments.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11

Similar content being viewed by others

References

  1. Van Rensburg R, Chazot P (2008) Alpha7 nicotinic acetylcholine receptors: molecular pharmacology and role in neuroprotection. Curr Anaesth Crit Care 19(4):202–214. doi:10.1016/j.cacc.2008.05.001

    Article  Google Scholar 

  2. Changeux JP, Taly A (2008) Nicotinic receptors, allosteric proteins and medicine. Trends Mol Med 14(3):93–102. doi:10.1016/j.molmed.2008.01.001

    CAS  Google Scholar 

  3. Celie PH, van Rossum-Fikkert SE, van Dijk WJ, Brejc K, Smit AB, Sixma TK (2004) Nicotine and carbamylcholine binding to nicotinic acetylcholine receptors as studied in AChBP crystal structures. Neuron 41(6):907–914. doi:10.1016/S0896-6273(04)00115-1

    Article  CAS  Google Scholar 

  4. Brejc K, van Dijk WJ, Klaassen RV, Schuurmans M, van Der Oost J, Smit AB, Sixma TK (2001) Crystal structure of an ACh-binding protein reveals the ligand-binding domain of nicotinic receptors. Nature 411(6835):269–276. doi:10.1038/35077011

    Article  CAS  Google Scholar 

  5. Capener CE, Kim HJ, Arinaminpathy Y, Sansom MS (2002) Ion channels: structural bioinformatics and modelling. Hum Mol Genet 11(20):2425–2433

    Article  CAS  Google Scholar 

  6. 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) The binding site of acetylcholine receptor as visualized in the X-Ray structure of a complex between alpha-bungarotoxin and a mimotope peptide. Neuron 32(2):265–275. doi:10.1016/S0896-6273(01)00461-5

    Article  CAS  Google Scholar 

  7. Bourne Y, Talley TT, Hansen SB, Taylor P, Marchot P (2005) Crystal structure of a Cbtx-AChBP complex reveals essential interactions between snake alpha-neurotoxins and nicotinic receptors. EMBO J 24(8):1512–1522. doi:10.1038/sj.emboj.7600620

    Article  CAS  Google Scholar 

  8. Dellisanti CD, Yao Y, Stroud JC, Wang ZZ, Chen L (2007) Crystal structure of the extracellular domain of nAChR alpha1 bound to alpha-bungarotoxin at 1.94 A resolution. Nat Neurosci 10(8):953–962. doi:10.1038/nn1942

    Article  CAS  Google Scholar 

  9. Unwin N (2005) Refined structure of the nicotinic acetylcholine receptor at 4A resolution. J Mol Biol 346(4):967–989. doi:10.1016/j.jmb.2004.12.031

    Article  CAS  Google Scholar 

  10. Karlin A (2002) Emerging structure of the nicotinic acetylcholine receptors. Nat Rev Neurosci 3(2):102–114. doi:10.1038/nrn731

    Article  CAS  Google Scholar 

  11. Schapira M, Abagyan R, Totrov M (2002) Structural model of nicotinic acetylcholine receptor isotypes bound to acetylcholine and nicotine. BMC Struct Biol 2(1):1–8. doi:10.1186/1472-6807-2-1

    Article  Google Scholar 

  12. Le Novère N, Grutter T, Changeux JP (2002) Models of the extracellular domain of the nicotinic receptors and of agonist- and Ca2+ -binding sites. Proc Natl Acad Sci USA 99(5):3210–3215. doi:10.1016/S0306-4522(00)00512-1

    Article  Google Scholar 

  13. Itier V, Bertrand D (2001) Neuronal nicotinic receptors: from protein structure to function. FEBS Lett 504(3):118–125. doi:10.1016/S0014-5793(01)02702-8

    Article  CAS  Google Scholar 

  14. Ivanov I, Cheng X, Sine SM, McCammon JA (2007) Barriers to ion translocation in cationic and anionic receptors from the Cys-loop family. J Am Chem Soc 129(26):8217–8224. doi:10.1021/ja070778l

    Article  CAS  Google Scholar 

  15. Parthiban M, Rajasekaran MB, Ramakumar S, Shanmughavel P (2009) Molecular modeling of human pentameric alpha(7) neuronal nicotinic acetylcholine receptor and its interaction with its agonist and competitive antagonist. J Biomol Struct Dyn 26(5):535–548. doi:10.1016/j.jmgm.2008.01.004

    CAS  Google Scholar 

  16. Sali A, Blundell TL (1993) Comparative protein modelling by satisfaction of spatial restraints. J Mol Biol 234(3):779–815. doi:10.1016/S1357-4310(95)91170-7

    Article  CAS  Google Scholar 

  17. Holm L, Park J (2000) DaliLite workbench for protein structure comparison. Bioinformatics 16(6):566–567

    Article  CAS  Google Scholar 

  18. Morris AL, MacArthur MW, Hutchinson EG, Thornton JM (1992) Stereochemical quality of protein structure coordinates. Proteins 12(4):345–364

    Article  CAS  Google Scholar 

  19. Kanagarajadurai K, Malini M, Bhattacharya A, Panicker M, Sowdhamini R (2009) Molecular modeling and docking studies of human 5-hydroxytryptamine 2A (5-HT2A) receptor for the identification of hotspots for ligand binding. Mol BioSyst 5:1877–1888, doi: 10.1039/b906391a

    Article  CAS  Google Scholar 

  20. Bairoch A, Apweiler R (1997) The SWISS-PROT protein sequence data bank and its supplement TrEMBL. Nucleic Acids Res 25(1):31–36

    Article  CAS  Google Scholar 

  21. Innis CA, Shi J, Blundell TL (2000) Evolutionary trace analysis of TGF-beta and related growth factors: implications for site-directed mutagenesis. Protein Eng 13(12):839–847

    Article  CAS  Google Scholar 

  22. Waterhouse AM, Procter JB, Martin DM, Clamp M, Barton GJ (2009) Jalview Version 2—a multiple sequence alignment editor and analysis workbench. Bioinformatics 25(9):1189–1191

    Article  CAS  Google Scholar 

  23. Lichtarge O, Bourne HR, Cohen FE (1996) An evolutionary trace method defines binding surfaces common to protein families. J Mol Biol 257(2):342–358. doi:10.1006/jmbi.1996.0167

    Article  CAS  Google Scholar 

  24. Lin F, Wang R (2009) Molecular modeling of the three-dimensional structure of GLP-1R and its interactions with several agonists. J Mol Model 15(1):53–65. doi:10.1007/s00894-008-0372-2

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors (M.P. and P.S.) thank the Department of Biotechonolgy-Bioinformatics Infrastructural Facility provided at Bharathiar University, Coimbatore. We also thank the National Centre for Biological Sciences, Bangalore, for infrastructural support.

Author information

Authors and Affiliations

  1. Department of Bioinformatics, Bioinformatics Centre and Computational Biology Laboratory, Bharathiar University, Coimbatore, 641064, India

    Marimuthu Parthiban & Piramanayagam Shanmughavel

  2. Tata Institute of Fundamental Research, National Centre for Biological Sciences, GKVK-UAS campus Bellary road, Bangalore, 560065, India

    Marimuthu Parthiban & Ramanathan Sowdhamini

Authors
  1. Marimuthu Parthiban
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Piramanayagam Shanmughavel
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ramanathan Sowdhamini
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ramanathan Sowdhamini.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Parthiban, M., Shanmughavel, P. & Sowdhamini, R. In silico point mutation and evolutionary trace analysis applied to nicotinic acetylcholine receptors in deciphering ligand-binding surfaces. J Mol Model 16, 1651–1670 (2010). https://doi.org/10.1007/s00894-010-0670-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00894-010-0670-3

Keywords

Search

Navigation