Journal of Computer-Aided Molecular Design

, Volume 19, Issue 6, pp 357–367 | Cite as

Modelling the Interaction of Catecholamines with the α1A Adrenoceptor Towards a Ligand-induced Receptor Structure

  • Gemma K. Kinsella
  • Isabel Rozas
  • Graeme W. Watson


Adrenoceptors are members of the important G protein coupled receptor family for which the detailed mechanism of activation remains unclear. In this study, we have combined docking and molecular dynamics simulations to model the ligand induced effect on an homology derived human α1A adrenoceptor. Analysis of agonist/α1A adrenoceptor complex interactions focused on the role of the charged amine group, the aromatic ring, the N-methyl group of adrenaline, the beta hydroxyl group and the catechol meta and para hydroxyl groups of the catecholamines. The most critical interactions for the binding of the agonists are consistent with many earlier reports and our study suggests new residues possibly involved in the agonist-binding site, namely Thr-174 and Cys-176. We further observe a number of structural changes that occur upon agonist binding including a movement of TM-V away from TM-III and a change in the interactions of Asp-123 of the conserved DRY motif. This may cause Arg-124 to move out of the TM helical bundle and change the orientation of residues in IC-II and IC-III, allowing for increased affinity of coupling to the G-protein.


α1A-adrenoceptor agonists molecular docking molecular dynamics receptor activation 


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  1. 1.
    Beduschi, M.C., Beduschi, R., Oesterling, J.E. 1998Urol.51861CrossRefPubMedGoogle Scholar
  2. 2.
    Ballesteros, J., Palczewski, K. 2001Curr. Opin. Drug Disc. Devel.4561Google Scholar
  3. 3.
    Okada, T., Palczewski, K. 2001Curr. Opin. Struct. Biol.11420CrossRefPubMedGoogle Scholar
  4. 4.
    Kinsella, G.K., Rozas, I., Watson, G.W. 2004Biochem. Biophys. Res. Commun.324916CrossRefPubMedGoogle Scholar
  5. 5.
    Hamaguchi, N., True, T., Saussy, D.L., Jeffs P.W., Biochemistry, 35 (1996) 14312.Google Scholar
  6. 6.
    Zhao, M., Hwa, J., Perez, D.M. 1996Mol. Pharmacol.501118PubMedGoogle Scholar
  7. 7.
    Waugh, D., Gaivin, R., Zuscik, M., Gonzalez-Cabrera, P., Ross, S., Yun, J., Perez, D. 2001J. Biol. Chem.2725366CrossRefGoogle Scholar
  8. 8.
    Cavalli, A., Fanelli, F., Taddei, C., Benedetti, P.G., Cotechia, S. 1996FEBS Lett.3999CrossRefPubMedGoogle Scholar
  9. 9.
    Piascik, M.T., Perez, D.M. 2001J. Pharmacol. Exp. Ther.2982Google Scholar
  10. 10.
    Kobilka, B. 2004Mol. Pharmacol.651060CrossRefPubMedGoogle Scholar
  11. 11.
    Gether, U., Kobilka, B.K. 1998J. Biol. Chem.27317979CrossRefPubMedGoogle Scholar
  12. 12.
    Javitch, J.A., Fu, D., Liapakis, G., Chen, J. 1997J. Biol. Chem.27218546CrossRefPubMedGoogle Scholar
  13. 13.
    Bea, I., Jaime, C., Kollman, P. 2002Theor. Chem. Acta.108286Google Scholar
  14. 14.
    Bissantz, C., Bernard, P., Hibert, M., Rognan, D. 2003Proteins505CrossRefPubMedGoogle Scholar
  15. 15.
    Chambers, J.J., Nichols, D.E. 2002J. Comput. Aided Mol. Des.16511CrossRefPubMedGoogle Scholar
  16. 16.
    Carmine, R., Molinari, P., Sbraccia, M., Ambrosio, C., Costa, T. 2004Mol. Pharmacol.662Google Scholar
  17. 17.
    Kuntz, I.D. 1992Science2571078PubMedGoogle Scholar
  18. 18.
    Sybyl6.9, Molecular Modelling System Tripos Associates. St. Louis, MO, USA.Google Scholar
  19. 19.
    Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scuseria, G.E., Robb, M.A., Cheeseman, J.R., Zakrzewski, V.G., Montgomery, J.A.,Jr., Stratmann, R.E., Burant, J.C., Dapprich, S., Millam, J.M., Daniels, A.D., Kudin, K.N., Strain, M.C., Farkas, O., Tomasi, J., Barone, V., Cossi, M., Cammi, R., Mennucci, B., Pomelli, C., Adamo, C., Clifford, S., Ochterski, J., Petersson, G.A., Ayala, P.Y., Cui, Q., Morokuma, K., Salvador, P., Dannenberg, J.J., Malick, D.K., Rabuck, A.D., Raghavachari, K., Foresman, J.B., Cioslowski, J., Ortiz, J.V., Baboul, A.G., Stefanov, B.B., Liu, G., Liashenko, A., Piskorz, P., Komaromi, I., Gomperts, R., Martin, R.L., Fox, D.J., Keith, T., Al-Laham, M.A., Peng, C.Y., Nanayakkara, A., Challacombe, M., Gill, P.M.W., Johnson, B., Chen, W., Wong, M.W., Andres, J.L., Gonzalez, C., Head-Gordon, M., Replogle, E.S., Pople, J.A. 2001Gaussian 98 (Rev A.11)Gaussian, IncPittsburgh, PAGoogle Scholar
  20. 20.
    Case, D.A., Pearlman, D.A., Caldwell, J.W., Cheatham, T.E.,III., Wang, J., Ross, W.S., Simmerling, C.L., Darden, T.A., Merz, K.M., Stanton, R.V., Cheng, A.L., Vincent, J.J., Crowley, M., Tsui, V., Gohlke, H., Radmer, R.J., Duan, Y., Pitera, J., Massova, I., Seibel, G.L., Singh, U.C., Weiner, P.K., Kollman, P.A. 2001Amber 7University of CaliforniaSan FranciscoGoogle Scholar
  21. 21.
    Wang, J., Cieplak, P., Kollman, P.A. 2000J. Comput. Chem.211049CrossRefGoogle Scholar
  22. 22.
    Berendsen, H.J.C., Postma, J.P.M., Gunsteren, W.F., DiNola, A., Haak, J.R. 1984J. Chem. Phys.813684CrossRefGoogle Scholar
  23. 23.
    Wymore, T. and Wong, T.C., 45th Annual Meeting of the Biophysical Society. Boston, MA, 2001.Google Scholar
  24. 24.
    Wang, J., Wolf, R.M., James, W., Caldwell, J.W., Kollman, P.A., Case, D.A. 2004J. Comp. Chem.251157CrossRefGoogle Scholar
  25. 25.
    Aldrich Library of FT-IR Spectra, 1 (1) 1296A.Google Scholar
  26. 26.
    Pedretti, A., Silva, M.E., Villa, L., Vistoli, G. 2000Biochem. Biophys. Res. Commun.319493CrossRefGoogle Scholar
  27. 27.
    Visiers, I., Ballesteros, J.A., Weinstein, H. 2002Methods Enzymol.343329PubMedGoogle Scholar
  28. 28.
    Palczewski, K., Kumasaka, T., Hori, T., Behnke, C.A., Motoshima, H., Fox, B.A., Trong, I.L., Teller, D.C., Okada, T., Stenkamp, R.E., Yamamoto, M., Miyano, M. 2000Science289739CrossRefPubMedGoogle Scholar
  29. 29.
    Luo, X., Zhang, D., Weinstein, H. 1994Protein Eng.71441PubMedGoogle Scholar
  30. 30.
    Scheer, A., Fanelli, F., Costa, T., Benedetti, P.G., Cotecchia, S. 1996Embo J.153566PubMedGoogle Scholar
  31. 31.
    Zhang, D., Weinstein, H. 1993J. Med. Chem.36934CrossRefPubMedGoogle Scholar
  32. 32.
    Farrens, D.L., Altenbach, C., Yang, K., Hubbell, W.L., Khorana, H.G. 1996Science274768CrossRefPubMedGoogle Scholar
  33. 33.
    Gether, U., Ballesteros, J.A., Seifert, R., Sanders-Bush, E., Weinstein, H., Kobilka, B.K. 1997J. Biol. Chem.2722587CrossRefPubMedGoogle Scholar
  34. 34.
    Gether, U., Lin, S., Ghanouni, P., Ballesteros, J.A., Weinstein, H., Kobilka, B.K. 1997Embo J.166737CrossRefPubMedGoogle Scholar
  35. 35.
    Gether, U., Lin, S., Kobilka, B.K. 1995J. Biol. Chem.27028268CrossRefPubMedGoogle Scholar
  36. 36.
    Javitch, J.A., Fu, D., Liapakis, G., Chen, J. 1997J. Biol. Chem.27218546CrossRefPubMedGoogle Scholar
  37. 37.
    Strader, C.D., Fong, T.M., Tota, M.R., Underwood, D., Dixon, R.A. 1994Annu Rev. Biochem.63101CrossRefPubMedGoogle Scholar
  38. 38.
    Wess, J. 1998Pharmacol. Therap.80231CrossRefGoogle Scholar
  39. 39.
    Zhou, W., Flanagan, C., Ballesteros, J.A., Konvocka, K., Davidson, J.S., Weinstein, H., Millar, R.P., Sealfon, S.C. 1994Mol. Pharmacol.45165PubMedGoogle Scholar
  40. 40.
    Sealfon, S.C., Chi, L., Ebersole, B.J., Rodic, V., Zhang, D., Ballesteros, J.A., Weinstein, H. 1995J. Biol. Chem.27016683CrossRefPubMedGoogle Scholar
  41. 41.
    Jongejan A., Bruysters M., Pardo L., Leurs R., Oral Presentation XVII Symposium of Medicinal Chemistry, 2004.Google Scholar

Copyright information

© Springer 2005

Authors and Affiliations

  • Gemma K. Kinsella
    • 1
  • Isabel Rozas
    • 1
    • 2
  • Graeme W. Watson
    • 1
  1. 1.Department of Chemistry, Trinity CollegeUniversity of DublinDublin 2Ireland
  2. 2.Centre for Synthesis and Chemical Biology, Trinity CollegeUniversity of DublinDublin 2Ireland

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