Probing the Topological Tolerance of Multimeric Protein Interactions: Evaluation of an Estrogen/Synthetic Ligand for FK506 Binding Protein Conjugate
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- 作者：Terry W. Moore ; Jillian R. Gunther ; John A. Katzenellenbogen
- 刊名：Bioconjugate Chemistry
- 出版年：2010
- 出版时间：October 20, 2010
- 年：2010
- 卷：21
- 期：10
- 页码：1880-1889
- 全文大小：330K
- 年卷期：v.21,no.10(October 20, 2010)
- ISSN：1520-4812
文摘
Bivalent small molecules composed of a targeting element and an element that recruits endogenous proteins have been shown to block protein−protein interactions in some systems. We have attempted to apply such an approach to disrupt the interaction of the estrogen receptor α with either its associated coactivators or its dimerization partner (i.e., another estrogen receptor). We show here that a conjugate capable of simultaneously binding both the estrogen receptor and a recruited protein (FK506 Binding Protein 12 kDa) is, however, incapable of disrupting the multimeric estrogen receptor dimer/coactivator complex both in vitro and in cell-based reporter gene assays. We postulate why it may not be possible to disrupt this particular protein−protein complex—as well as other systems having high topological tolerance—with such bivalent inhibitors.