Skip to main content
SpringerLink
Log in

Investigating the Putative Binding-mode of GABA and Diazepam within GABAA Receptor Using Molecular Modeling

  • Published:
The Protein Journal Aims and scope Submit manuscript

Abstract

The three-dimensional structure of the GABAA receptor that included the ligand/agonist binding site was constructed and validated by using molecular modeling technology. Moreover, the putative binding-mode of GABA and diazepam with GABAA receptor were investigated by means of docking studies. Based on an rmsd-tolerance of 1.0 Å, the docking of GABA to α1/β2 interface resulted in three multi-member conformational clusters and model 2 was supported by homologous sequence alignment data and experimental evidence. On the other hand, the docking of diazepam to α1/γ2 interface revealed five multi-member conformational clusters in the binding site and model 1 seemed to represent the correct orientation of diazepam in the binding site.

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

Similar content being viewed by others

Abbreviations

GABA:

γ-Aminobutyric acid

GABAA :

Receptors: type A receptors of GABA

BZ:

Benzodiazepines

AchBP:

Acetylcholine-binding protein

LGIC:

Ligand-gated ion channels

DOPE:

Discrete optimized potential energy

ADT:

AutoDockTools

HEK:

Human embryonic kidney

nACh receptor:

Nicotinic acetylcholine receptor

Refernences

  1. Barnard EA (1992) Trends Biochem Sci 17:368–374

    Article  CAS  Google Scholar 

  2. Schofield PR, Darlison MG, Fujita N, Burt DR, Stephenson FA, Rodriguez H, Rhee LM, Ramachandran J, Reale V, Glencorse TA (1987) Nature 328:221–227

    Article  CAS  Google Scholar 

  3. Shi H, Tsang SY, Tse MK, Xu Z, Xue H (2003) Protein Sci, 12:2642–2646

    Article  CAS  Google Scholar 

  4. Buhr A, Bianchi MT, Baur R, Courtet P, Pignay V, Boulenger JP, Gallati S, Hinkle DJ, Macdonald RL, Sigel E (2002) Hum Genet 111:154–160

    Article  CAS  Google Scholar 

  5. Wafford KA (2005) Curr Opin Pharmacol 5:47–52

    Article  CAS  Google Scholar 

  6. Barnard EA, Skolnick P, Olsen RW, Mohler H, Sieghart W, Biggio G, Braestrup C, Bateson AN, Langer SZ (1998) Pharmacol Rev 50:291–313

    CAS  Google Scholar 

  7. Sieghart W (1995) Pharmacol Rev 47:181–234

    CAS  Google Scholar 

  8. Korpi ER, Grunder G, Luddens H (2002) Prog Neurobiol 67:113–159

    Article  CAS  Google Scholar 

  9. Minier F, Sigel E (2004) Proc Natl Acad Sci USA 101:7769–7774

    Article  CAS  Google Scholar 

  10. 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 

  11. Smit AB, Syed NI, Schaap D, van Minnen J, Klumperman J, Kits KS, Lodder H, van der Schors RC, van Elk R, Sorgedrager B, Brejc K, Sixma TK, Geraerts WP A (2001) Nature 411:261–268

    Article  CAS  Google Scholar 

  12. Campagna-Slater V, Weaver DF (2006) J Mol Graph Model (Epub ahead of print)

  13. Ernst M, Bruckner S, Boresch S, Sieghart WC (2005) Mol Pharmacol 68:1291–1300

    Article  CAS  Google Scholar 

  14. Harrison NJ, Lummis SC R (2006) J Mol Model 12:317–324

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  16. Trudell J (2002) Biochim Biophys Acta 1565:91–96

    Article  CAS  Google Scholar 

  17. Reeves DC, Sayed MF, Chau PL, Price KL, Lummis SC (2003) Biophys J 84:2338–2344

    CAS  Google Scholar 

  18. Thompson JD, Higgins DG, Gibson TJ (1994) Nucleic Acids Res 22:4673–4680

    Article  CAS  Google Scholar 

  19. Sali A, Blundell TL (1993) J Mol Biol 234:779–815

    Article  CAS  Google Scholar 

  20. Eramian D, Shen MY, Devos D, Melo F, Sali A, Marti-Renom MA (2006) Protein Sci 15:1653–1566

    Article  CAS  Google Scholar 

  21. Fiser A, Do RK, Sali A (2000) Protein Sci 9:1753–1773

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  24. Morris AL, MacArthur MW, Hutchinson EG, Thornton JM (1992) Proteins 12:345–364

    Article  CAS  Google Scholar 

  25. Morris GM, Goodsell DS, Halliday RS, Huey R, Hart WE, Belew RK, Olson AJ (1998) J Comput Chem 19:1639–1662

    Article  CAS  Google Scholar 

  26. Allinger NL (1977) J Am Chem Soc 99:8127–8134

    Article  CAS  Google Scholar 

  27. Gasteiger J, Marsili M (1980) Tetrahedron 36:3219–3288,

    Article  CAS  Google Scholar 

  28. Sanner MF (1999) J Mol Graph Model 17:57–61

    CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  30. Wallace AC, Laskowski RA, Thornton JM (1995) Protein Eng 8:127–134

    Article  CAS  Google Scholar 

  31. Klausberger T, Sarto I, Ehya N, Fuchs K, Furtmuller R, Mayer B, Huck S, Sieghart W (2001) J Neurosci 21:9124–9133

    CAS  Google Scholar 

  32. Taylor PM, Connolly CN, Kittler JT, Gorrie GH, Hosie A, Smart TG, Moss SJ (2000) J Neurosci 20:1297–1306

    CAS  Google Scholar 

  33. Berezhnoy D, Nyfeler Y, Gonthier A, Schwob H, Goeldner M, Sigel E (2004) J BiolChem 279:3160–3168

    CAS  Google Scholar 

  34. Boileau AJ, Evers AR, Davis AF, Czajkowski C (1999) J Neurosci 19:4847–4854

    CAS  Google Scholar 

  35. Cromer BA, Morton CJ, Parker MW (2002) Trends Biochem Sci 27:280–287

    Article  CAS  Google Scholar 

  36. Hartvig L, Lukensmejer B, Liljefors T, Dekermendjian K (2000) J Neurochem 75:1746–1753

    Article  CAS  Google Scholar 

  37. Smith GB, Olsen RW (1994) J Biol Chem 269:20380–20387

    CAS  Google Scholar 

  38. Sigel E, Buhr A (1997) Trends Pharmacol Sci 18:425–429

    CAS  Google Scholar 

  39. Sigel E, Baur R, Kellenberger S, Malherbe P, (1992) EMBO J 11:2017–2023

    CAS  Google Scholar 

  40. Drafts BC, Fisher JL (2004) J Pharmacol Exp Ther 309:1108–1115

    Article  CAS  Google Scholar 

  41. Sedelnikova A, Smith CD, Zakharkin SO, Davis D, Weiss DS, Chang Y (2005) J Biol Chem 280:1535–1542

    Article  CAS  Google Scholar 

  42. Boileau AJ, Newell JG, Czajkowski C (2002) J Biol Chem 277:2931-2937

    Google Scholar 

  43. Beene DL, Brandt GS, Zhong W, Zacharias NM, Lester HA, Dougherty DA (2002) Biochemistry 41:10262–10269

    Article  CAS  Google Scholar 

  44. 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 

  45. Amin J, Weiss DS (1993) Nature 366:565–569

    Article  CAS  Google Scholar 

  46. Wagner DA, Czajkowski C (2001) J Neurosci 21:67–74

    CAS  Google Scholar 

  47. Grutter T, Changeux JP (2001) Trends Biochem Sci 26:459–463

    Article  CAS  Google Scholar 

  48. Pritchett DB, Seeburg PH (1990) J Neurochem 54:1802–1804

    Article  CAS  Google Scholar 

  49. Wieland HA, Luddens H, Seeburg PH (1992) J Biol Chem 267:1426–1429

    CAS  Google Scholar 

  50. Buhr A, Schaerer MT, Baur R, Sigel E (1997) Mol Pharmacol 52:676–682

    CAS  Google Scholar 

  51. Wang D, Chiara DC, Xie Y, Cohen JB (2000) J Biol Chem 275:28666–28674

    Article  CAS  Google Scholar 

  52. Buhr A, Baur R, Sigel E (1997) J Biol Chem 272:11799–11804

    Article  CAS  Google Scholar 

  53. Kucken AM, Wagner DA, Ward PR, Teissere JA, Boileau AJ, Czajkowski C (2000) Mol Pharmacol 57:932–939

    CAS  Google Scholar 

  54. Buhr A, Sigel E (1997) Proc Natl Acad Sci USA 16:8824–8829

    Article  Google Scholar 

  55. Mihic SJ, Whiting PJ, Klein RL, Wafford KA, Harris RA (1994) J Biol Chem 269:32768–32773

    Google Scholar 

Download references

Acknowledgments

The present work was financially supported by the National Natural Science Foundation of China (No. 20672113) and the National 973 Program of China (Contract No. 2003CB114400).

Author information

Authors and Affiliations

  1. National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing, 100080, P.R. China

    Suqin Ci, Tianrui Ren & Zhiguo Su

  2. Graduate University of Chinese Academy of Sciences, Beijing, 100049, P.R. China

    Suqin Ci

Authors
  1. Suqin Ci
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tianrui Ren
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zhiguo Su
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tianrui Ren.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ci, S., Ren, T. & Su, Z. Investigating the Putative Binding-mode of GABA and Diazepam within GABAA Receptor Using Molecular Modeling. Protein J 27, 71–78 (2008). https://doi.org/10.1007/s10930-007-9109-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10930-007-9109-9

Keywords

Search

Navigation