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

Joshua S. Grimley, Denise A. Chen, Laura A. Banaszynski, Thomas J. Wandless

Research output: Contribution to journalArticle

14 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)759-761
Number of pages3
JournalBioorganic and Medicinal Chemistry Letters
Volume18
Issue number2
DOIs
StatePublished - Jan 15 2008

Keywords

  • Degradation
  • Protein engineering
  • Protein stability

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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