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Evolutionary trace analysis of ionotropic glutamate receptor sequences and modeling the interactions of agonists with different NMDA receptor subunits

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Abstract

The ionotropic N-methyl-d-aspartate (NMDA) receptor is of importance in neuronal development, functioning, and degeneration in the mammalian central nervous system. The functional NMDA receptor is a heterotetramer comprising two NR1 and two NR2 or NR3 subunits. We have carried out evolutionary trace (ET) analysis of forty ionotropic glutamate receptor (IGRs) sequences to identify and characterize the residues forming the binding socket. We have also modeled the ligand binding core (S1S2) of NMDA receptor subunits using the recently available crystal structure of NR1 subunit ligand binding core which shares ~40% homology with other NMDA receptor subunits. A short molecular dynamics simulation of the glycine-bound form of wild-type and double-mutated (D481N; K483Q) NR1 subunit structure shows considerable RMSD at the hinge region of S1S2 segment, where pore forming transmembrane helices are located in the native receptor. It is suggested that the disruption of domain closure could affect ion-channel activation and thereby lead to perturbations in normal animal behavior. In conclusion, we identified the amino acids that form the ligand-binding pocket in many ionotropic glutamate receptors and studied their hydrogen bonded and nonbonded interaction patterns. Finally, the disruption in the S1S2 domain conformation (of NR1 subunit- crystal structure) has been studied with a short molecular dynamics simulation and correlated with some experimental observations.

Figure The figure shows the binding mechanism of glutamate with NR2B subunit of the NMDA receptor. Glutamate is shown in cpk, hydrogen bonds in dotted lines and amino acids in blue. The amino acids shown here are within a 4-Å radius of the ligand (glutamate)

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References

  1. Dingledine R, Borges K, Bowie D, Traynelis SF (1999) Pharmacol Rev 51:7–61

    CAS  PubMed  Google Scholar 

  2. Cull-Candy S, Brickley S, Farrant M (2001) Curr Opin Neurobiol 11:327–335

    Article  CAS  PubMed  Google Scholar 

  3. Mayer ML, Westbrook GL, Guthrie PB (1984) Nature 309:261–263

    CAS  PubMed  Google Scholar 

  4. Madison DV, Malenka RC, Nicoll RA (1991) Annu Rev Neurosci 14:379–397

    Article  CAS  PubMed  Google Scholar 

  5. Monyer H, Sprengel R, Schoepfer R, Herb A, Higuchi M, Lomeli H, Burnashev N, Sakmann B Seeburg PH (1992) Science 256:1217–1221

    CAS  PubMed  Google Scholar 

  6. Kutsuwada T, Kashiwabuchi N, Mori H, Sakimura K, Kushiya E, Araki K, Meguro H, Masaki H, Kumanishi T, Arakawa M (1992) Nature 358:36–41

    Article  CAS  PubMed  Google Scholar 

  7. Johnson JW, Ascher P (1987) Nature 325:529–531

    Article  CAS  PubMed  Google Scholar 

  8. Kleckner NW, Dingledine R (1988) Science 241:835–837

    CAS  PubMed  Google Scholar 

  9. Laube B, Hirai H, Sturgess M, Betz H, Kuhse J (1997) Neuron 18:493–503

    Article  CAS  PubMed  Google Scholar 

  10. Kemp JA, Bluethmann H, Kew JN (2002) 22:6713–6723

    PubMed  Google Scholar 

  11. Anson LC, Chen PE, Wyllie DJ, Colquhoun D, Schoepfer R (1998) J Neurosci 18:581–589

    CAS  PubMed  Google Scholar 

  12. Chatterton JE, Awobuluyi M, Premkumar LS, Takahashi H, Talantova M, Shin Y, Cui J, Tu S, Sevarino KA, Nakanishi N, Tong G, Lipton SA, Zhang D (2002) Nature 415:793-798

    CAS  PubMed  Google Scholar 

  13. Matsuda K, Kamiya Y, Matsuda S, Yuzaki M (2002) Brain Res Mol Brain Res 100:43–52

    Article  CAS  PubMed  Google Scholar 

  14. Das S, Sasaki YF, Rothe T, Premkumar LS, Takasu M, Crandall JE, Dikkes P, Conner DA, Rayudu PV, Cheung W, Chen HS, Lipton SA, Nakanishi N (1998) Nature 393:377–381

    Article  CAS  PubMed  Google Scholar 

  15. Perez-Otano I, Schulteis CT, Contractor A, Lipton SA, Trimmer JS, Sucher NJ, Heinemann SF (2001) J Neurosci 21:1228–1237

    CAS  PubMed  Google Scholar 

  16. Ciabarra AM, Sullivan JM, Gahn LG, Pecht G, Heinemann S, Sevarino KA (1995) J Neurosci 15:6498–6508

    CAS  PubMed  Google Scholar 

  17. Furukawa H, Gouaux E (2003) EMBO J 22:2873–2885

    Article  CAS  PubMed  Google Scholar 

  18. Armstrong N, Gouaux E (2000) Neuron 28:165–181

    Article  CAS  PubMed  Google Scholar 

  19. Stern-Bach Y, Bettler B, Hartley M, Sheppard PO, O’Hara PJ, Heinemann SF (1994) Neuron 13:1345–1357

    Article  CAS  PubMed  Google Scholar 

  20. Oh BH, Pandit J, Kang CH, Nikaido K, Gokcen S, Ames GF, Kim SH (1993) J Biol Chem 268:11348–1155

    CAS  PubMed  Google Scholar 

  21. Lummis SC, Fletcher EJ, Green T (2002) Neuropharmacology 42:437–443

    Article  CAS  PubMed  Google Scholar 

  22. Tikhonova IG, Baskin II, Palyulin VA, Zefirov NS (2003) J Med Chem 46:1609–1616

    Article  CAS  PubMed  Google Scholar 

  23. Tikhonova IG, Baskin II, Palyulin VA, Zefirov NS, Bachurin SO (2002) J Med Chem 45:3836–3843

    Article  CAS  PubMed  Google Scholar 

  24. Kuusinen A, Arvola M, Keinanen K (1995) EMBO J 14:6327–6332

    CAS  PubMed  Google Scholar 

  25. Ivanovic A, Reilander H, Laube B, Kuhse J (1998) J Biol Chem 273:19933–19937

    Article  CAS  PubMed  Google Scholar 

  26. Keinanen K, Jouppila A, Kuusinen A (1998) Biochem J 330:1461–1467

    CAS  PubMed  Google Scholar 

  27. Lichtarge O, Bourne HR, Cohen FE (1996) Proc Natl Acad Sci USA 93:7507–7511

    Article  CAS  PubMed  Google Scholar 

  28. Forrest D, Yuzaki M, Soares HD, Ng L, Luk DC, Sheng M, Stewart CL, Morgan JI, Connor JA, Curran T (1994) Neuron 13:325–338

    Article  CAS  PubMed  Google Scholar 

  29. Miyamoto Y, Yamada K, Noda Y, Mori H, Mishina M, Nabeshima T (2001) J Neurosci 21:750–757

    CAS  PubMed  Google Scholar 

  30. Li Y, Erzurumlu RS, Chen C, Jhaveri S, Tonegawa S (1994) Cell 76:427–437

    Article  CAS  PubMed  Google Scholar 

  31. Mohn AR, Gainetdinov RR, Caron MG, Koller BH (1999) Cell 98:427–436

    Article  CAS  PubMed  Google Scholar 

  32. Kiefer F, Jahn H, Koester A, Montkowski A, Reinscheid RK, Wiedemann K (2003) Biol Psychiatry 53:345–351

    Article  CAS  PubMed  Google Scholar 

  33. Ballard TM, Pauly-Evers M, Higgins GA, Ouagazzal AM, Mutel V, Borroni E, Kemp JA, Bluethmann H, Kew JN (2002) J Neurosci 22:6713–6723

    PubMed  Google Scholar 

  34. Kew JN, Koester A, Moreau JL, Jenck F, Ouagazzal AM, Mutel V, Richards JG, Trube G, Fischer G, Montkowski A, Hundt W, Reinscheid RK, Pauly-Evers M, Kemp JA, Bluethmann H (2000) J Neurosci 20:4037–4049

    CAS  PubMed  Google Scholar 

  35. Altschul SF, Madden TL, Schaffer AA, Zhang J, Zhang Z, Miller W, Lipman DJ (1997) Nucleic Acids Res 25:3389–3402

    CAS  PubMed  Google Scholar 

  36. Rost B, Sander C (1993) J Mol Biol 232:584–599

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  39. Luthy R, Bowie JU, Eisenberg D (1992) Nature 356:83–85

    Article  CAS  PubMed  Google Scholar 

  40. Laskowski RA, MacArthur MW, Moss DS, Thornton JM (1993) Jol Appl Crystal 26:283–291

    Article  CAS  Google Scholar 

  41. All tools utilized herein were accessed and utilized as implemented in Insight II-97.5, Accelrys (http://www.accelrys.com)

  42. Kleywegt GJ, Jones TA (1997) Methods Enzymol 277:525–545

    Article  CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  44. Sayle RA, Milner-White EJ (1995) Trends Biochem Sci 20:374

    Article  CAS  PubMed  Google Scholar 

  45. Chothia C, Lesk AM (1986) EMBO J 5:823–826

    CAS  PubMed  Google Scholar 

  46. Zvelebil MJ, Barton GJ, Taylor WR, Sternberg MJ (1987) J Mol Biol 195:957–961

    CAS  PubMed  Google Scholar 

  47. Baldwin JM (1993) EMBO J 12:1693–1703

    CAS  PubMed  Google Scholar 

  48. Zvelebil MJ, Sternberg MJ (1988) Protein Eng 2:127–138

    CAS  PubMed  Google Scholar 

  49. Arinaminpathy Y, Biggin PC, Shrivastava IH, Sansom MS (2003) FEBS Lett 553:321–327

    Article  CAS  PubMed  Google Scholar 

  50. Arinaminpathy Y, Sansom MS, Biggin PC (2002) Biophys J 82:676–683

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Dr. Chittaranjan Andrade and Dr. Innis Axel for language correction of the manuscript.

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Authors and Affiliations

  1. Department of Psychopharmacology, National Institute of Mental Health and Neuro Sciences (NIMHANS), 560029, Bangalore, India

    Mathias-Costa Blaise & Nithyananda Pradhan

  2. National Centre for Biological Sciences (NCBS), TIFR, UAS-GKVK Campus, 560065, Bangalore, India

    Ramanathan Sowdhamini & Metpally Raghu Prasad Rao

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  1. Mathias-Costa Blaise
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  2. Ramanathan Sowdhamini
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  3. Metpally Raghu Prasad Rao
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  4. Nithyananda Pradhan
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Correspondence to Nithyananda Pradhan.

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Blaise, MC., Sowdhamini, R., Rao, M.R.P. et al. Evolutionary trace analysis of ionotropic glutamate receptor sequences and modeling the interactions of agonists with different NMDA receptor subunits. J Mol Model 10, 305–316 (2004). https://doi.org/10.1007/s00894-004-0196-7

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  • DOI: https://doi.org/10.1007/s00894-004-0196-7

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