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Probing the topological tolerance of multimeric protein interactions: evaluation of an estrogen/synthetic ligand for FK506 binding protein conjugate.

ABSTRACT: 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 ? 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.

SUBMITTER: Moore TW

PROVIDER: S-EPMC2967433 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Probing the topological tolerance of multimeric protein interactions: evaluation of an estrogen/synthetic ligand for FK506 binding protein conjugate.

Moore Terry W TW Gunther Jillian R JR Katzenellenbogen John A JA

Bioconjugate chemistry 20101001 10

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 ...[more]

PMID: 20919698

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