Skip to main content
Springer Nature Link
Log in

In silico analysis of the histaprodifen induced activation pathway of the guinea-pig histamine H1-receptor

  • Published:
Journal of Computer-Aided Molecular Design Aims and scope Submit manuscript

Abstract

The binding of (partial) agonists in the binding pocket of biogenic amine receptors induces a conformational change from the inactive to the active state of the receptors. There is only little knowledge about the binding pathways of ligands into binding pocket on molecular level. So far, it was not possible with molecular dynamic simulations to observe the ligand binding and receptor activation. Furthermore, there is nearly nothing known, in which state of ligand binding, the receptor gets activated. The aim of this study was to get more detailed insight into the process of ligand binding and receptor activation. With the recently developed LigPath algorithm, we scanned the potential energy surface of the binding process of dimeric histaprodifen, a partial agonist at the histamine H1-receptor, into the guinea pig histamine H1-receptor, taking also into account the receptor activation. The calculations exhibited large conformational changes of Trp6.48 and Phe6.55 during ligand binding and receptor activation. Additionally, conformational changes were also observed for Phe6.52, Tyr6.51 and Phe6.44. Conformational changes of Trp6.48 and Phe6.52 are discussed in literature as rotamer toggle switch in context with receptor activation. Additionally, the calculations indicate that the binding of dimeric histaprodifen, accompanied by receptor activation is energetically preferred. In general, this study gives new, theoretical insights onto ligand binding and receptor activation on molecular level.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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

Similar content being viewed by others

References

  1. Pierce KL, Premont RT, Lefkowitz RJ (2002) Nat Rev Mol Cell Biol 9:639–650

    Article  Google Scholar 

  2. Kristiansen K (2004) Pharmacol Ther 103:21–80

    Article  CAS  Google Scholar 

  3. Gether U, Kobilka BK (1998) J Biol Chem 273:17979–17982

    Article  CAS  Google Scholar 

  4. Kobilka BK, Deupi X (2007) Trends Pharmacol Sci 28:397–406

    Article  CAS  Google Scholar 

  5. Kobilka BK (2007) Biochim Biophys Acta 1768:794–807

    Article  CAS  Google Scholar 

  6. Kobilka BK, Deupi X (2007) Trends Pharm Sci 28:397–406

    Article  CAS  Google Scholar 

  7. Bartfai T, Benovic J, Bockaert J, Bond RA, Bouvier M, Christopoulos A, Civelli O, Devi LA, George SR, Inui A, Kobilka BK, Leurs R, Neubig R, Pin JP, Quirion R, Roques BP, Sakmar TP, Seifert R, Stenkam RE, Strange PG (2004) Nat Rev Drug Discov 3:577–626

    Article  Google Scholar 

  8. Ghanouni P, Steenhuis JJ, Farrens DL, Kobilka BK (2001) Proc Natl Acad Sci USA 98:5997–6002

    Article  CAS  Google Scholar 

  9. Xie SX, Ghorai P, Ye QZ, Buschauer A, Seifert R (2006) J Pharmacol Exp Ther 317:139–146

    Article  CAS  Google Scholar 

  10. Wittmann HJ, Seifert R, Strasser A (2009) Mol Pharmacol 76:25–37

    Article  CAS  Google Scholar 

  11. Bhattacharya S, Hall SE, Li H, Vaidehi N (2008) Biophys J 84:2027–2042

    Article  Google Scholar 

  12. Bhattacharya S, Hall SE, Vaidehi N (2008) J Mol Biol 382:539–555

    Article  CAS  Google Scholar 

  13. Schertler GF (2005) Curr Opin Struct Biol 15:408–415

    Article  CAS  Google Scholar 

  14. Gabilondo AM, Cornelius K, Lohse MJ (1996) Eur J Pharmacol 307:243–250

    Article  CAS  Google Scholar 

  15. Liapakis G, Ballesteros JA, Papchristou S, Chan WC, Chen X, Javitch JA (2000) J Biol chem 275:37779–37788

    Article  CAS  Google Scholar 

  16. Chen S, Lin F, Xu M, Rie RP, Novotny J, Graham RM (2002) Biochemistry 41:6045–6053

    Article  CAS  Google Scholar 

  17. Jongejan A, Bruysters M, Ballesteros JA, Haaksma E, Bakker RA, Pardo L, Leurs R (2005) Nat Chem Biol 1:98–103

    Article  CAS  Google Scholar 

  18. Javitch JA, Fu D, Liapakis G, Chen J (1997) J Biol Chem 272:18546–18549

    Article  CAS  Google Scholar 

  19. Rasmussen SGF, Jensen AD, Liapakis G, Ghanouni P, Javitch JA, Gether U (1999) Mol Pharmacol 56:175–184

    CAS  Google Scholar 

  20. Shi L, Liapakis G, Xu R, Guarnieri F, Ballesteros JA, Javitch JA (2002) J Biol Chem 277:40989–40996

    Article  CAS  Google Scholar 

  21. Vilardaga JP, Steinmeyer R, Harms GS, Lohse MJ (2005) Nat Chem Biol 1:25–28

    Article  CAS  Google Scholar 

  22. Farrens D, Altenbach C, Yan K, Hubbell W, Khorana HG (1996) Science 274:768–770

    Article  CAS  Google Scholar 

  23. Ward SDC, Hamdan FF, Bloodworth LM, Wess J (2002) J Biol Chem 277:2247–2257

    Article  CAS  Google Scholar 

  24. Dunham TD, Farrens DL (1999) J Biol Chem 274:1683–1690

    Article  CAS  Google Scholar 

  25. Altenbach C, Klein-Seetharaman J, Cai K, Khorana HG, Hubbell WL (2001) Biochemistry 40:15493–15500

    Article  CAS  Google Scholar 

  26. Shen J, Li W, Liu G, Tang Y, Jiang H (2009) J Phys Chem B 113:10436–10444

    Article  CAS  Google Scholar 

  27. Wang T, Duan Y (2009) J Mol Biol 392:1102–1115

    Article  CAS  Google Scholar 

  28. Straßer A, Wittmann HJ (2007) J Mol Model 13:209–218

    Article  Google Scholar 

  29. Straßer A, Wittmann HJ (2007) J Comput Aided Mol Des 21:499–509

    Article  Google Scholar 

  30. Bakker RA, Jongejan A, Sansuk K, Hacksell U, Timmerman H, Brann MR, Weiner DM, Pardo L, Leurs R (2008) Mol Pharmacol 73:94–103

    Article  CAS  Google Scholar 

  31. Straßer A, Wittmann HJ, Seifert R (2008) J Pharmacol Exp Ther 326:783–791

    Article  Google Scholar 

  32. Straßer A, Wittmann HJ, Kunze M, Elz S, Seifert R (2009) Mol Pharmacol 75:454–465

    Article  Google Scholar 

  33. Bruysters M, Jongejan A, Gillard M, van de Manakker F, Bakker R, Chatelain P, Leurs R (2005) Mol Pharmacol 67:1045–1052

    Article  CAS  Google Scholar 

  34. Jongejan A, Leurs R (2005) Arch Pharm Chem Life Sci 338:248–259

    Article  CAS  Google Scholar 

  35. Bruysters M, Pertz HH, Teunissen A, Bakker RA, Gillard M, Chatelain P, Schunack W, Timmerman H, Leurs R (2004) 487:55–63

  36. Menghin S, Pertz HH, Kramer K, Seifert R, Schunack W, Elz S (2003) J Med Chem 46:5458–5470

    Article  CAS  Google Scholar 

  37. Seifert R, Wenzel Seifert K, Bürckstümmer T, Pertz HH, Schunack W, Dove S, Buschauer A, Elz S (2003) J Pharmacol Exp Ther 305:1104–1115

    Article  CAS  Google Scholar 

  38. Straßer A, Striegl B, Wittmann HJ, Seifert R (2008) J Pharmacol Exp Ther 324:60–71

    Article  Google Scholar 

  39. Ballesteros JA, Shi L, Javitch JA (2001) Mol Pharmacol 60:1–19

    CAS  Google Scholar 

  40. Palczewski K, Kumasaka T, Hori T, Behnke CA, Motoshima H, Fox BA, Le Trong I, Teller DC, Okada T, Stenkamp RE, Yamamoto M, Miyano M (2000) Science 289:739–745

    Article  CAS  Google Scholar 

  41. Cherezov V, Rosenbaum DM, Hanson MA, Rasmussen SG, Thian FS, Kobilka TS, Choi HJ, Kuhn P, Weis WI, BK Kobilka, Stevens RC (2007) Science 318:1258–1265

    Article  CAS  Google Scholar 

  42. Rasmussen SGF, Choi HJ, Rosenbaum DM, Kobilka TS, Thian FS, Edwards PC, Burghammer M, Ratnala VRP, Sanishvili R, Fischetti RF, Schertler GFX, Weis WI, Kobilka BR (2007) Nature 450:383–387

    Article  CAS  Google Scholar 

  43. Rosenbaum DM, Cherezov V, Hanson MA, Rasmussen SGF, Thian FS, Kobilka BS, Choi HJ, Yao XJ, Weis WI, Stevens RC, Kobilka BK (2007) Science 318:1266–1273

    Article  CAS  Google Scholar 

  44. Niv MY, Skrabanek L, Filizola M, Weinstein H (2006) J Comput Aided Mol Des 20:437–448

    Article  CAS  Google Scholar 

  45. Scheerer P, Park JH, Hildebrand PW, Kim YJ, Krauss N, Choe HW, Hofmann KP, Ernst OP (2008) Nature 455:497–503

    Article  CAS  Google Scholar 

  46. Oostenbrink C, Villa A, Mark AE, van Gunsteren WF (2004) J Comput Chem 25:1656–1676

    Article  CAS  Google Scholar 

  47. van der Spool D, Lindahl E, Hess B, Groenhof G, Mark AE, Berendsen HJC (2005) J Comput Chem 26:1701–1718

    Article  Google Scholar 

  48. Crocker E, Eilers M, Ahuja S, Hornak V, Hirshfeld A, Sheves M, Smith SO (2006) J Mol Biol 357:163–172

    Article  CAS  Google Scholar 

  49. Singh R, Hurst DP, Barnett-Norris J, Lynch DL, Reggio PH, Guarnieri F (2002) J Peptide Res 60:357–370

    Article  CAS  Google Scholar 

  50. Colson AO, Perlman JH, Jinsi-Parimoo A, Nussenzveig DR, Osman R, Gershengorn MC (1998) Mol Pharmacol 54:968–978

    CAS  Google Scholar 

Download references

Acknowledgments

We thank the DFG (Deutsche Forschungsgemeinschaft) for further support of this project.

Author information

Authors and Affiliations

  1. Department of Pharmaceutical and Medicinal Chemistry, Faculty of Chemistry and Pharmacy, University of Regensburg, Regensburg, Germany

    Andrea Straßer

  2. Faculty of Chemistry and Pharmacy, University of Regensburg, Regensburg, Germany

    Hans-Joachim Wittmann

Authors
  1. Andrea Straßer
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Hans-Joachim Wittmann
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to Andrea Straßer.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Straßer, A., Wittmann, HJ. In silico analysis of the histaprodifen induced activation pathway of the guinea-pig histamine H1-receptor. J Comput Aided Mol Des 24, 759–769 (2010). https://doi.org/10.1007/s10822-010-9372-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10822-010-9372-2

Keywords