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Synthesis and analysis of stabilizing ligands for FKBP-derived destabilizing domains.

ABSTRACT: We recently identified mutants of the human FKBP12 protein that are unstable and rapidly degraded when expressed in mammalian cells. We call these FKBP mutants destabilizing domains (DDs), because their instability is conferred to any protein fused to the DDs. A cell-permeable ligand binds tightly to the DDs and prevents their degradation, thus providing small molecule control over intracellular protein levels. We now report the synthesis and functional characterization of a stabilizing ligand called Shield-2. The synthesis of Shield-2 is efficient, and this ligand binds to the FKBP(F36V) protein with a dissociation constant of 29 nM.

SUBMITTER: Grimley JS

PROVIDER: S-EPMC2245802 | biostudies-literature | 2008 Jan

REPOSITORIES: biostudies-literature

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Synthesis and analysis of stabilizing ligands for FKBP-derived destabilizing domains.

Grimley Joshua S JS Chen Denise A DA Banaszynski Laura A LA Wandless Thomas J TJ

Bioorganic & medicinal chemistry letters 20071117 2

We recently identified mutants of the human FKBP12 protein that are unstable and rapidly degraded when expressed in mammalian cells. We call these FKBP mutants destabilizing domains (DDs), because their instability is conferred to any protein fused to the DDs. A cell-permeable ligand binds tightly to the DDs and prevents their degradation, thus providing small molecule control over intracellular protein levels. We now report the synthesis and functional characterization of a stabilizing ligand c ...[more]

PMID: 18039574

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