Molecular Diversity

, Volume 16, Issue 3, pp 441–451 | Cite as

In silico design of peptidic inhibitors targeting estrogen receptor alpha dimer interface

  • Sandipan Chakraborty
  • Shawn Cole
  • Nicholas Rader
  • Candace King
  • R. Rajnarayanan
  • P. K. Biswas
Full-Length Paper


Human estrogen receptor alpha (ERα), which acts as a biomarker and as a therapeutic target for breast cancers, is activated by agonist ligands and co-activator proteins. Selective estrogen receptor modulators (SERM) act as antagonists in specific tissues and tamoxifen, a SERM, has served as a drug for decades for ERα-positive breast cancers. However, the ligand-selective and tissue-specific response of ERα biological activity and the resistance to tamoxifen treatment in advanced stages of ERα-positive breast cancers underscores the need to find a ligand-independent inhibitor for ERα. Here we present a ligand-independent approach of inhibiting ERα transactivation targeting its dimerization—a key process of ERα biological activity. Using in silico techniques, we first elucidated the hydrogen bond interactions involved in dimerization and identified three interfacial sequence motifs, where sequence I (DKITD) and sequence II (QQQHQRLAQ) of one monomer form hydrogen bonding with sequence II and sequence I of the second monomer, respectively, and sequence III (LSHIRHMSNK) hydrogen bonds with the same from the second monomer. Studying the structural stability and the binding affinity of the peptides derived from these sequence motifs, we found that an extended and ARG mutated version (LQQQHQQLAQ) of sequence II can act as a suitable template for designing peptidic inhibitors. It provides additional structural stability and interacts more strongly with ERα dimer interface groove formed by helices 9 and 10/11 and prevent ERα dimerization. Our result provides a novel therapeutic designing pipeline for ligand-independent inhibition of ERα.


Estrogen receptor alpha Selective estrogen receptor modulators Bio-molecular modeling and simulations Sequence motif Peptidic inhibitors Helical stability 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Supplementary material

11030_2012_9378_MOESM1_ESM.doc (195 kb)
ESM 1 (DOC 195kb)


  1. 1.
    Beato M, Herrlich P, Schutz G (1995) Steroid hormone receptors: many actors in search of a plot. Cell 83: 851–857. doi: 10.1016/0092-8674(95)90201-5 PubMedCrossRefGoogle Scholar
  2. 2.
    Levin ER (2001) Cell localization, physiology, and nongenomic actions of estrogen receptors. J Appl Physiol 91: 1860–1867PubMedGoogle Scholar
  3. 3.
    Vidal O, Lindberg M, Sävendahl L, Lubahn DB, Ritzen EM, Gustafsson JÅ, Ohlsson C (1999) Disproportional body growth in female estrogen receptor-α-inactivated mice. Biochem Biophys Res Commun 19: 569–571. doi: 10.1006/bbrc.1999.1711 CrossRefGoogle Scholar
  4. 4.
    Stender JD, Kim K, Charn TH, Komm B, Chang KCN, Kraus WL, Benner C, Glass CK, Katzenellenbogen BS (2010) Genome-wide analysis of estrogen receptor α DNA binding and tethering mechanisms identifies runx1 as a novel tethering factor in receptor-mediated transcriptional activation. Mol Cell Biol 30: 3943–3955. doi: 10.1128/MCB.00118-10 PubMedCrossRefGoogle Scholar
  5. 5.
    Hall JM, Couse JF, Korach KS (2001) The multifaceted mechanisms of estradiol and estrogen receptor signaling. J Biol Chem 276: 36869–36872. doi: 10.1074/jbc.R100029200 PubMedCrossRefGoogle Scholar
  6. 6.
    Nadal A, Diaz M, Valverde MA (2001) The estrogen trinity: membrane, cytosolic, and nuclear effects. News Physiol Sci 16: 251–255PubMedGoogle Scholar
  7. 7.
    Bjornstrom L, Sjoberg M (2005) Mechanisms of estrogen receptor signaling: convergence of genomic and nongenomic actions on target genes. Mol Endocrinol 19: 833–842. doi: 10.1210/me.2004-0486 PubMedCrossRefGoogle Scholar
  8. 8.
    Horwitz KB (1999) Bringing estrogen receptors under control. Breast Cancer Res 1: 5–7. doi: 10.1186/bcr3 PubMedCrossRefGoogle Scholar
  9. 9.
    Shiau AK, Barstad D, Loria PM, Cheng L, Kushner PJ, Agard DA, Greene GL (1998) The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen. Cell 95: 927–937. doi: 10.1016/S0092-8674(00)81717-1 PubMedCrossRefGoogle Scholar
  10. 10.
    Gottardis MM, Robinson SP, Satyaswaroop PG, Jordan VC (1988) Contrasting actions of tamoxifen on endometrial and breast tumor growth in the athymic mouse. Cancer Res 48: 812–815PubMedGoogle Scholar
  11. 11.
    Jordan VC (1998) Antiestrogenic action of raloxifene and tamoxifen: today and tomorrow. J Natl Cancer Inst 90: 967–971. doi: 10.1093/jnci/90.13.967 PubMedCrossRefGoogle Scholar
  12. 12.
    Ruff M, Gangloff M, Wurtz JM, Moras D (2000) Estrogen receptor transcription and transactivation Structure–function relationship in DNA- and ligand-binding domains of estrogen receptors. Breast Cancer Res 2: 353–359. doi: 10.1186/bcr80 PubMedCrossRefGoogle Scholar
  13. 13.
    Kumar V, Green S, Stack G, Berry M, Jim JR, Chambon P (1987) Functional domains of the human estrogen receptor. Cell 51: 941–951. doi: 10.1016/0092-8674(87)90581-2 PubMedCrossRefGoogle Scholar
  14. 14.
    Kraus WL, McInerney EM, Katzenellenbogen BS (1995) Ligand dependent transcriptionally productive association of the amino-and carboxyl-terminal regions of a steroid hormone nuclear receptor. Proc Natl Acad Sci USA 92: 12314–12318PubMedCrossRefGoogle Scholar
  15. 15.
    Gandini O, Kohno H, Curtis S, Korach KS (1997) Two transcription activation functions in the amino terminus of the mouse estrogen receptor that are affected by the carboxy terminus. Steroids 62: 508–515. doi: 10.1016/S0039-128X(97)00001-9 PubMedCrossRefGoogle Scholar
  16. 16.
    Warnmark A, Treuter E, Wright PHA, Gustafsson J (2003) Activation functions 1 and 2 of nuclear receptors: molecular strategies for transcriptional activation. Mol Endocr 17: 1901–1909. doi: 10.1210/me.2002-0384 CrossRefGoogle Scholar
  17. 17.
    Wansa KDSA, Harris JM, Muscat GEO (2002) The activation function-1 domain of Nur77/NR4A1 mediates transactivation, cell specificity and coactivator recruitment. J Biol Chem 277: 33001–33011. doi: 10.1074/jbc.M203572200 PubMedCrossRefGoogle Scholar
  18. 18.
    Meegan MJ, Lloyd DG (2003) Advances in the science of estrogen receptor modulation. Curr Med Chem 10: 181–210PubMedCrossRefGoogle Scholar
  19. 19.
    Schwabe JWR, Chapman L, Finch JT, Rhodes D (1993) The crystal structure of the estrogen receptor DNA-binding domain bound to DNA: how receptors discriminate between their response elements. Cell 75: 567–578. doi: 10.1016/0092-8674(93)90390-C PubMedCrossRefGoogle Scholar
  20. 20.
    Bourguet W, Ruff M, Chambon P, Gronemeyer H, Moras D (1995) Crystal structure of the ligand-binding domain of the human nuclear receptor RXR-a. Nature 375: 377–382. doi: 10.1038/375377a0 PubMedCrossRefGoogle Scholar
  21. 21.
    Wurtz JM, Bourguet W, Renaud JP, Vivat V, Chambon P, Moras D, Gronemeyer H (1996) A canonical structure for the ligand-binding domain of nuclear receptors. Nat Struct Biol 3: 87–94. doi: 10.1038/nsb0196-87 PubMedCrossRefGoogle Scholar
  22. 22.
    Shiau AK, Barstad D, Loria PM, Cheng L, Kushner PJ, Agard DA, Greene GL (1998) The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen. Cell 95: 927–937. doi: 10.1016/S0092-8674(00)81717-1 PubMedCrossRefGoogle Scholar
  23. 23.
    Brzozowski AM, Pike AC, Dauter Z, Hubbard RE, Bonn T, Engstrom O, Ohman L, Greene G L, Gustafsson JA, Carlquist M (1997) Molecular basis of agonism and antagonism in the estrogen receptor. Nature 389: 753–758. doi: 10.1038/39645 PubMedCrossRefGoogle Scholar
  24. 24.
    Dutia BM, Frame MC, Subak-Sharpe JH, Clark WN, Marsden HS (1986) Specific inhibition of herpesvirus ribonucleotide reductase by synthetic peptides. Nature 321: 439–441. doi: 10.1038/321439a0 PubMedCrossRefGoogle Scholar
  25. 25.
    Divita G, Restle T, Goody RS, Chermann JC, Baillon JG (1994) Inhibition of HIV1 reverse transcriptase dimerization using synthetic peptides derived from the connection domain. J Biol Chem 269: 13080–13083PubMedGoogle Scholar
  26. 26.
    Yudt MR, Koide S (2001) Preventing estrogen receptor action with dimer-interface peptides. Steroids 66: 549–558. doi: 10.1016/S0039-128X(00)00224-5 PubMedCrossRefGoogle Scholar
  27. 27.
    Sali A, Blundell TL (1993) Comparative protein modelling by satisfaction of spatial restraints. J Mol Biol 234: 779–815. doi: 10.1006/jmbi.1993.1626 PubMedCrossRefGoogle Scholar
  28. 28.
    Humphrey W, Dalke A, Schulten K (1996) VMD—visual molecular dynamics. J Mol Graphics 14: 33–38. doi: 10.1016/0263-7855(96)00018-5 CrossRefGoogle Scholar
  29. 29.
    Berendsen HJC, Spoel DVD, Drunen RV (1995) GROMACS: a message-passing parallel molecular dynamics implementation. Comput Phys Commun 91: 45–56. doi: 10.1016/0010-4655(95)00042-E CrossRefGoogle Scholar
  30. 30.
    Lindahl E, Hess B, Spoel DVD (2001) GROMACS 3.0 a package for molecular simulation and trajectory analysis. J Mol Model 7: 306–317. doi: 10.1007/s008940100045 Google Scholar
  31. 31.
    Jorgensen WL, Rives T (1988) Development and testing of the OPLS all-atom force field on conformational energetic and properties of organic liquids. J Am Chem Soc 110: 1657–1666. doi: 10.1021/ja00214a001 CrossRefGoogle Scholar
  32. 32.
    Hess B, Bekker H, Berendsen HJC, Fraaije JGEM (1997) LINCS: A linear constraint solver for molecular simulations. J Comp Chem 18: 1463–1472. doi: 10.1002/(SICI)1096-987X(199709)18:12<1463::AID-JCC4>3.0.CO;2-H CrossRefGoogle Scholar
  33. 33.
    DeLano WL (2002) The PyMOL molecular graphics system. DeLano Scientific, Palo AltoGoogle Scholar
  34. 34.
    Bryson K, McGuffin LJ, Marsden RL, Ward JJ, Sodhi JS, Jones DT (2005) Protein structure prediction servers at University College London. Nucl Acids Res 33 (Web server issue):W36–W38. doi: 10.1093/nar/gki410
  35. 35.
    Capriotti E, Fariselli P, Casadio R (2005) I-Mutant2.0: predicting stability changes upon mutation from the protein sequence or structure. Nucl Acids Res 33 (Web server issue):W306–W310. doi: 10.1093/nar/gki375
  36. 36.
    Baker NA, Sept D, Joseph S, Holst MJ, McCammon JA (2001) Electrostatics of nanosystems: application to microtubules and the ribosome. Proc Natl Acad Sci USA 98: 10037–10041. doi: 10.1073/pnas.181342398 PubMedCrossRefGoogle Scholar
  37. 37.
    Tamrazi A, Carlson KE, Daniels JR, Hurth KM, Katzenellenbogen JA (2002) Estrogen receptor dimerization: ligand binding regulates dimer affinity and dimer dissociation rate. Mol Endocrinol 16: 2706–2719. doi: 10.1210/me.2002-0250 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2012

Authors and Affiliations

  • Sandipan Chakraborty
    • 1
  • Shawn Cole
    • 1
  • Nicholas Rader
    • 1
  • Candace King
    • 2
  • R. Rajnarayanan
    • 3
  • P. K. Biswas
    • 1
  1. 1.Laboratory of Computational Biophysics & Bioengineering Department of PhysicsTougaloo CollegeTougalooUSA
  2. 2.Department of BiologyTougaloo CollegeTougalooUSA
  3. 3.Department of Pharmacology and ToxicologyUniversity of BuffaloBuffaloUSA

Personalised recommendations