Ligand-selective inhibition of the interaction of steroid receptor coactivators and estrogen receptor isoforms

Timothy R. Geistlinger, Andrea C. McReynolds, R. Kiplin Guy

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

Abstract

Ligand-dependent nuclear hormone receptor (NR) signaling requires direct interaction between NR and the steroid receptor coactivators (SRC). Herein we utilize a library of SRC2 peptidomimetics to select for specific inhibitors of the interaction of SRC2 with the two estrogen receptor (ER) isoforms, ERα and ERβ, in the presence of three different ligands: 17β-estradiol, diethylstilbesterol, and genistein. The pattern of inhibitor selectivity for each ER isoform varied depending upon which ligand was present, thus demonstrating that the ligands exert unique allosteric effects upon the surface of the SRC binding pocket. Several of the lead compounds are highly (>100-fold) selective for blocking the binding of SRC2 to ERα, in preference to ERβ, in the presence of one ligand and therefore may prove useful for decoupling ERβ signaling from ERα signaling.

Original languageEnglish
Pages (from-to)273-281
Number of pages9
JournalChemistry and Biology
Volume11
Issue number2
DOIs
StatePublished - Feb 2004

Bibliographical note

Funding Information:
We acknowledge the DOD (predoctoral fellowship of T.R.G. #DAM-17-00-1-0191), the Sidney Kimmel Foundation for Cancer Research, the HHMI Research Resources Program (#76296-549901), the Academic Senate of UCSF, NIH (R01 #DK58080), and the Sandler Foundation. We thank Anang Shelat for coding the volumetric calculator. We dedicate this paper to Dr. Irwin Kuntz in celebration of his retirement. The authors declare that they have no competing financial interests.

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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